_:b372877431 . _:b372877878 . _:b372877879 . _:b372877880 . _:b372877672 . _:b372877881 . _:b372877572 "3"^^ . . _:b372877882 . _:b372877430 . _:b372877883 . _:b372877884 . _:b372877885 . _:b372877575 "3"^^ . _:b372877425 . _:b372877886 . _:b372877887 . _:b372877856 . _:b372878031 . _:b372877857 . _:b372877574 "3"^^ . _:b372877319 . _:b372877424 . _:b372877858 . . _:b372877859 . _:b372877860 . _:b372877861 . _:b372877569 "3"^^ . _:b372877427 . _:b372877862 . _:b372877863 . _:b372877973 . _:b372877864 . . _:b372877865 . _:b372877568 "3"^^ . _:b372877426 . _:b372877823 . _:b372877866 . _:b372877867 . _:b372877868 . _:b372877506 . _:b372877571 "3"^^ . _:b372877869 . _:b372877437 . _:b372877997 . _:b372877870 . _:b372877871 . _:b3291424 . _:b372877840 . _:b372877841 . _:b372877570 "3"^^ . _:b372877436 . _:b372877842 . _:b372877493 . _:b372877843 . _:b372877844 . _:b372877845 . _:b372877581 "3"^^ . _:b372877439 . _:b3291378 "To avoid any indirect effects of MMP-9 deficiency that could occur in the kainate model because of the well known role of MMP-9 in neuronal death (Jourquin et al., >>2003<<; for review see Yong, 2005), we decided to investigate a chemical kindling model that, in contrast to the kainate model, does not involve neurodegeneration." . _:b372877846 . _:b372877847 . _:b372877848 . _:b372877849 . . _:b372877580 "3"^^ . _:b372877438 . _:b372877850 . _:b372877851 . _:b372877852 . . _:b372877295 . _:b372877583 "3"^^ . _:b372877853 . _:b372877433 . _:b372877854 . _:b372877855 . _:b3291375 . _:b372877865 . _:b372877824 . _:b372877294 . _:b372877582 "3"^^ . _:b372877825 . _:b372877432 . . _:b372877826 . _:b372877827 . _:b372877454 . . _:b372878005 . _:b372877828 . _:b372877829 . _:b372877577 "3"^^ . _:b372877435 . _:b372877830 . _:b372877831 . _:b372877832 . _:b372877984 . . _:b372877576 "3"^^ . _:b372877833 . _:b372877434 . . . _:b372877834 . _:b372877835 . _:b372877836 . _:b3291368 "Dendritic spines were identified using a guinea pig anti-ProSAP2/Shank antibody and a PSD marker (Boeckers et al., >>1999<<) together with rhodamine-phalloidin (Sigma-Aldrich), which binds to spine F-actin, or with a guinea pig anti-drebrin antibody (Fitzgerald)." . _:b372877837 . . _:b372877579 "3"^^ . _:b372877445 . _:b372877838 . _:b372877839 . _:b372877578 "3"^^ . _:b372877444 . _:b372877301 . _:b372877589 "3"^^ . _:b372877679 . _:b372877447 . . _:b372877300 . _:b372877588 "3"^^ . _:b372877446 . _:b372877797 . _:b372877303 . _:b372877591 "3"^^ . _:b372877441 . _:b372877873 . _:b372877503 . _:b372877302 . _:b372877590 "3"^^ . _:b372877440 . _:b372877297 . _:b372877585 "3"^^ . _:b372877443 . _:b372877296 . _:b372877584 "3"^^ . _:b372877442 . _:b372877299 . _:b372877587 "3"^^ . _:b372877495 . _:b372877453 . _:b372877891 . _:b372877913 . _:b3291394 "Although there is evidence that excitation-driven MMP-9 activation can be deleterious to neurons (Jourquin et al., >>2003<<), this cannot apply to DG granule cells, which are known to survive even the very intense kainate-evoked status epilepticus (Sperk, 1994)." . _:b372878032 . _:b372877298 . _:b372877586 "3"^^ . _:b372878033 . _:b372877452 . _:b372878034 . _:b372878035 . _:b3291386 "Epileptogenesis in the kainate-treated hippocampus begins within \u223C1 wk after the insult when sprouting mossy fibers start to make recurrent synapses with granule cell dendrites (Suzuki et al., 1997; Sutula et al., 1998; Ben-Ari, >>2001<<). To test whether MMP-9 activity may play a role in aberrant synaptogenesis, we first used rat organotypic hippocampal slices subjected either to kainate excitotoxicity or picrotoxin stimulation and treated with a specific MMP-9 inhibitor." . _:b372878036 . _:b372877309 . _:b372877862 . _:b372877597 "3"^^ . _:b372878037 . _:b372877455 . . _:b372877308 . _:b372877596 "3"^^ . _:b372877454 . _:b372877954 . _:b372877311 . _:b372877857 . _:b372877599 "3"^^ . _:b372877449 . . . . _:b372878016 . . _:b372877598 "3"^^ . _:b372878017 . _:b372877310 . _:b372877448 . . _:b372878018 . _:b372878019 . _:b372878020 . _:b3291423 "Indeed, the presence of MMP-9 in astrocytes (by double labeling with GFAP; Szklarczyk et al., 2002) and in oligodendrocytes under nonstimulated conditions (Oh et al., >>1999<<) has been previously described." . . _:b372877305 . _:b372878037 . _:b372877593 "3"^^ . _:b372878021 . _:b372877451 . _:b372878022 . _:b372878023 . _:b3291400 "In contrast, the density of NMDAR only shows modest changes with synapse size (Takumi et al., >>1999<<). Accordingly, long-term synaptic potentiation, which is associated with transformation from silent (NMDAR only\u2013containing) to fully excitable (NMDAR- and AMPA-containing) synapses is associated with the enlargement and/or reshaping of" . . _:b372878024 . _:b372877304 . _:b372877592 "3"^^ . _:b372878025 . _:b372877450 . _:b372878026 . _:b372878027 . _:b372878028 . _:b372877307 . _:b372877595 "3"^^ . _:b372878029 . _:b372877461 . _:b372878030 . _:b372878031 . _:b3291387 . _:b372878000 . _:b372877306 . _:b372877594 "3"^^ . _:b372878001 . _:b372877460 . _:b372878002 . _:b372878003 . _:b372878004 . _:b372878005 . _:b372877605 "3"^^ . _:b372877463 . _:b372878006 . _:b372878007 . _:b372877376 . _:b372878008 . _:b372877577 . _:b372877604 "3"^^ . _:b372878009 . _:b372877720 . _:b372878010 . _:b372877462 . _:b372877702 . . . _:b372878011 . _:b372878012 . _:b372878013 . _:b372877607 "3"^^ . _:b372877457 . _:b372878014 . _:b372878015 . _:b372877984 . _:b372877985 . _:b372877606 "3"^^ . _:b372877456 . _:b372877405 . _:b372877321 . _:b372877986 . _:b372877987 . _:b372877988 . _:b372877989 . _:b372877649 . _:b372877601 "3"^^ . _:b372877459 . _:b372877990 . _:b372877991 . _:b372877992 . _:b372877673 . _:b372877993 . _:b372877600 "3"^^ . _:b372877458 . . _:b372877994 . _:b372877995 . _:b3291378 . _:b372877996 . _:b372877997 . _:b372877603 "3"^^ . _:b372877469 . _:b372877998 . _:b372877433 . _:b372877999 . _:b372877968 . _:b372877969 . _:b372877602 "3"^^ . _:b372877492 . _:b372877970 . _:b372877468 . _:b372877971 . _:b372877972 . _:b372877613 "2"^^ . _:b372877973 . _:b372877471 . _:b3291410 . _:b372877844 . . _:b372877974 . _:b372877975 . . _:b372877976 . _:b372877612 "2"^^ . _:b372877977 . _:b372877470 . _:b372877978 . _:b372877979 . _:b372877980 . _:b372877615 "2"^^ . _:b372877981 . _:b372877465 . _:b372877982 . _:b372877983 . _:b372877952 . _:b372877614 "2"^^ . _:b372877953 . _:b372877464 . . _:b372877954 . _:b372877955 . _:b372877956 . _:b372877609 "2"^^ . _:b372877957 . _:b372877467 . _:b3291401 "which is associated with transformation from silent (NMDAR only\u2013containing) to fully excitable (NMDAR- and AMPA-containing) synapses is associated with the enlargement and/or reshaping of the dendritic spines (Toni et al., >>2001<<; Matsuzaki et al., 2004). Notably, if these changes are precluded by the use of substances disrupting the F-actin cytoskeleton, potentiation does not occur (Fukazawa et al., 2003)." . _:b372877958 . . _:b372877959 . _:b372877960 . _:b372877961 . _:b372877608 "3"^^ . _:b372877466 . _:b372877962 . _:b372877963 . . _:b372877964 . _:b372877964 . _:b372877611 "2"^^ . _:b372877965 . _:b372877750 . _:b372877477 . _:b372877966 . _:b372877967 . _:b372877610 "2"^^ . _:b372877698 . _:b372877476 . _:b372877421 . _:b3291403 "Notably, if these changes are precluded by the use of substances disrupting the F-actin cytoskeleton, potentiation does not occur (Fukazawa et al., >>2003<<). It is of interest in this regard that MMP-9 appears to be involved specifically in the late phase of long-term potentiation (Nagy et al., 2006; Okulski et al., 2007). It is possible that the failure of MMP-9\u2013deficient neurons to develop" . . _:b372877621 "2"^^ . _:b372877479 . _:b372877620 "2"^^ . _:b372877504 . _:b372877478 . . _:b372877915 . _:b372877623 "2"^^ . _:b372877473 . . _:b372877622 "2"^^ . . _:b372877472 . _:b372877998 . _:b372878020 . . _:b372877617 "2"^^ . _:b372877475 . _:b372877616 "2"^^ . . _:b3291355 "Status epilepticus in rats was induced by intraperitoneal injection of 10 mg/kg and the animals were observed for up to 6 h, as previously described (Szklarczyk et al., >>2002<<)." . _:b372877585 . _:b372877474 . _:b372877619 "2"^^ . . _:b372877485 . _:b3291425 . _:b372877479 . _:b372877618 "2"^^ . _:b372877829 . _:b372877484 . _:b372877629 "2"^^ . _:b372877487 . _:b372877511 . _:b372877628 "2"^^ . _:b372877486 . _:b3291358 . _:b372877631 "2"^^ . . _:b372877481 . _:b372877630 "2"^^ . _:b372877480 . _:b372877625 "2"^^ . _:b372877485 . . _:b372877483 . _:b3291377 . _:b3291429 "Besides being engaged in normal processes, tPA and neuropsin were implicated in the pathogenesis of epilepsy (Wu et al., >>2000<<; for review see Shiosaka, 2004)." . _:b372877624 "2"^^ . _:b372877482 . _:b372877974 . _:b372877627 "2"^^ . _:b372877493 . _:b372877626 "2"^^ . _:b372877492 . _:b372877327 . _:b372877637 "2"^^ . _:b3291390 . _:b372877495 . . _:b372877382 . _:b372877636 "2"^^ . _:b372877494 . _:b372877639 "2"^^ . _:b3291334 . _:b372877690 . _:b372877489 . _:b372877574 . _:b372877638 "2"^^ . _:b372877367 . _:b372877488 . _:b372877633 "2"^^ . _:b372877491 . _:b3291388 . . _:b372877497 . _:b372877632 "2"^^ . _:b372877945 . _:b372877747 . _:b372877490 . _:b372877635 "2"^^ . _:b372877501 . _:b3291353 . _:b372877634 "2"^^ . _:b372877500 . . _:b372877645 "2"^^ . . . _:b372877503 . _:b372877644 "2"^^ . _:b372877502 . . _:b372877647 "2"^^ . . _:b372877497 . _:b372877646 "2"^^ . _:b372877496 . _:b372877641 "2"^^ . . _:b372877499 . _:b372877640 "2"^^ . _:b372877498 . _:b372877643 "2"^^ . _:b372877509 . _:b372877642 "2"^^ . _:b372877352 . _:b372877508 . _:b372877653 "2"^^ . _:b372877511 . _:b3291360 . _:b372877652 "2"^^ . . _:b372877510 . _:b372877582 . _:b372877655 "2"^^ . _:b372877505 . _:b372877939 . _:b372878026 . _:b372877654 "2"^^ . _:b372877504 . . _:b372877649 "2"^^ . . . _:b372877507 . _:b372877648 "2"^^ . _:b372877506 . _:b372877651 "2"^^ . _:b372877517 . _:b372877650 "2"^^ . _:b372877336 . _:b372877516 . _:b372877661 "2"^^ . _:b372877519 . . . . _:b372877660 "2"^^ . _:b372877518 . . _:b372877663 "2"^^ . _:b372877513 . _:b372877717 . _:b372877662 "2"^^ . _:b372877654 . _:b372877512 . _:b372877657 "2"^^ . _:b372877515 . _:b372877667 . _:b372877656 "2"^^ . _:b372877514 . _:b372877659 "2"^^ . _:b372877635 . _:b3291404 "It is of interest in this regard that MMP-9 appears to be involved specifically in the late phase of long-term potentiation (Nagy et al., >>2006<<; Okulski et al., 2007)." . _:b372877525 . _:b372877658 "2"^^ . _:b372877524 . _:b372877669 "2"^^ . _:b372877710 . _:b372877527 . _:b372877668 "2"^^ . _:b372877526 . _:b372877671 "2"^^ . _:b3291362 "Louis, MO; Betsuyaku et al., >>2000<<; see subsequent sentences for working dilutions)." . _:b372877602 . _:b372877521 . _:b3291397 "These are novel observations that force us to revise the current concepts regarding the roles of MMP-9 in synaptic plasticity, concepts which are derived mainly from functional studies and light microscopic data (Nagy et al., >>2006<<; Bozdagi et al., 2007)." . _:b372877670 "2"^^ . _:b372877337 . _:b372877520 . . _:b372877665 "2"^^ . _:b372877523 . . _:b372877664 "2"^^ . _:b372877522 . _:b372877667 "2"^^ . _:b372877928 . _:b372878010 . _:b372877326 . _:b372877533 . _:b372877666 "2"^^ . _:b372877532 . _:b372877725 . _:b372878033 . _:b372877677 "2"^^ . _:b372877535 . . . _:b372877676 "2"^^ . _:b372877534 . _:b372877679 "2"^^ . _:b372877529 . . . . _:b372877678 "2"^^ . _:b372877528 . _:b372877673 "2"^^ . _:b372877531 . . _:b372877672 "2"^^ . _:b372877444 . _:b372877530 . . _:b372877420 . _:b372877675 "2"^^ . _:b372877541 . _:b372877674 "2"^^ . . _:b372877540 . . _:b372877685 "2"^^ . . _:b372877311 . _:b372877543 . _:b372877642 . _:b372877684 "2"^^ . _:b372877542 . . _:b372877687 "2"^^ . _:b372877307 . _:b372877537 . _:b372877686 "2"^^ . _:b372877536 . _:b372877681 "2"^^ . _:b372877539 . _:b372877680 "2"^^ . _:b372877835 . _:b372877538 . _:b372877660 . _:b372877683 "2"^^ . . _:b372877549 . _:b372877682 "2"^^ . _:b372877548 . _:b3291376 . _:b372877693 "2"^^ . _:b372877892 . _:b372877551 . _:b372877692 "2"^^ . _:b372877550 . _:b372877695 "2"^^ . . _:b372877545 . _:b372877694 "2"^^ . _:b372877544 . _:b372877689 "2"^^ . . _:b372877547 . _:b372877688 "2"^^ . _:b372877546 . _:b372877691 "2"^^ . _:b372878024 . _:b372877557 . _:b372877690 "2"^^ . _:b372877556 . _:b372877888 . _:b372877573 . _:b372877701 "2"^^ . . _:b372877559 . . _:b372877700 "2"^^ . . _:b372877558 . . _:b372877703 "2"^^ . _:b372877528 . _:b372877553 . _:b372877702 "2"^^ . _:b372877552 . _:b3291402 . _:b372877697 "2"^^ . _:b372877555 . _:b372877696 "2"^^ . . _:b372877554 . . . _:b372877699 "2"^^ . _:b372877565 . _:b372877698 "2"^^ . _:b372877564 . . _:b372877509 . _:b372877709 "2"^^ . _:b372877567 . _:b3291399 . _:b372877708 "2"^^ . _:b3291360 "MMP-9 inhibition was achieved by growing the cultures in the presence of the specific MMP-9 inhibitor S24994 (Hanessian et al., >>2001<<) at a 100-nM concentration." . _:b372877897 . _:b372877566 . _:b372877711 "2"^^ . _:b372877469 . _:b372877561 . . _:b372877710 "2"^^ . _:b372877560 . . _:b372877705 "2"^^ . _:b372877563 . _:b372877704 "2"^^ . _:b372877632 . _:b3291356 . _:b372877562 . . _:b372877459 . _:b372877707 "2"^^ . _:b372877600 . _:b372877706 "2"^^ . . _:b372877717 "2"^^ . . _:b372877899 . . _:b372877716 "2"^^ . _:b372877719 "2"^^ . . _:b3291356 "The adult male mice were anesthetized with 1.3 ml/kg ketamine and 1.25 ml/kg xylazine and subjected to stereotactic unilateral injection with 1 nmol kainate in 0.3 \u03BCl PBS into the amygdala (Wu et al., >>2000<<). The coordinates of the injection were the following: bregma, 1.6 mm; medial\u2013lateral, 3.3 mm; and dorsoventral, 4.5 mm." . . _:b372877718 "2"^^ . _:b372877713 "2"^^ . . . . _:b372877712 "2"^^ . . _:b372877715 "2"^^ . _:b372877714 "2"^^ . _:b3291352 . . . _:b372877725 "2"^^ . . . _:b3291431 "In fact, behavioral, anatomical, and molecular events that are associated with kainate- and kindling-induced epileptogenesis in rats and mice largely reproduce the corresponding events in human TLE (Ben-Ari, >>2001<<). An essential feature of the human disease captured by both models is aberrant synaptic plasticity. In this paper, we show that the formation of aberrant synaptic networks depends on MMP-9. Because these networks keep progressing," . _:b372877795 . _:b372877724 "2"^^ . . . _:b372877975 . _:b372877346 . . _:b372877727 "2"^^ . _:b372877726 "2"^^ . _:b372877623 . _:b372877721 "2"^^ . _:b372877720 "2"^^ . _:b372877788 . _:b372877723 "2"^^ . _:b372877668 . _:b372877722 "2"^^ . . "10.1083%2Fjcb.200708213" . _:b372877604 . _:b372877733 "2"^^ . _:b372877564 . _:b372877732 "2"^^ . . _:b372877735 "2"^^ . _:b372877734 "2"^^ . . _:b372877729 "2"^^ . . . _:b372877728 "2"^^ . _:b3291344 . _:b372877731 "2"^^ . . _:b372877345 . _:b372877730 "2"^^ . _:b372877468 . _:b372877789 . _:b372877852 . _:b372877741 "2"^^ . _:b3291367 . _:b372877740 "2"^^ . _:b372877651 . _:b3291348 . . . _:b372877743 "2"^^ . . _:b372877606 . . _:b372877742 "2"^^ . . _:b3291350 . . _:b372877570 . _:b372877737 "2"^^ . _:b372877736 "2"^^ . _:b372878022 . _:b372877739 "2"^^ . _:b372877738 "2"^^ . _:b372877801 . _:b372877742 . _:b372877749 "2"^^ . _:b372877757 . _:b372877527 . _:b372877748 "2"^^ . _:b372877343 . . _:b372877751 "2"^^ . . _:b372877832 . . . _:b372877633 . _:b372877750 "2"^^ . . _:b372877745 "2"^^ . _:b372877744 "2"^^ . . _:b372877747 "2"^^ . _:b372877746 "2"^^ . _:b372877757 "2"^^ . . _:b3291383 "Because MMP-9 KO mice are resistant to the excitotoxic effect of intraperitoneally administered kainate (unpublished data), probably because of their C57BL/6 genetic background (McKhann et al., >>2003<<), we made unilateral kainate injections into the amygdala (according to Wu et al. [2000]) that did result in status epilepticus, followed by characteristic hippocampal CA1-CA3 and hilar degeneration on the injected, but not contralateral," . _:b372877756 "2"^^ . _:b372877759 "2"^^ . . _:b372877758 "2"^^ . _:b372877753 "2"^^ . _:b372877818 . _:b372877843 . _:b372877752 "2"^^ . _:b372877471 . _:b372877755 "2"^^ . _:b372877601 . _:b372877754 "2"^^ . _:b372877549 . _:b372877344 . _:b372877765 "2"^^ . . . _:b372877786 . _:b372877764 "2"^^ . _:b372877547 . _:b372877767 "2"^^ . . . _:b372877766 "2"^^ . . _:b372877914 . _:b372877761 "2"^^ . _:b3291389 . _:b372878027 . _:b372877745 . _:b372877760 "2"^^ . _:b372877811 . . _:b3291409 "MMP-9 could be involved because laminin is one of its substrates and tPA is known to act upstream of MMP-9 (Sternlicht and Werb, >>2001<<). Cadherins and integrins are two major families of synaptic adhesion proteins that have been strongly implicated in spine physiology (Benson et al., 2000). Outside the brain, members of these families are known to function as either MMP" . _:b372877389 . _:b372877942 . _:b372877763 "2"^^ . _:b372877762 "2"^^ . _:b372877427 . _:b372877773 "2"^^ . _:b372877869 . _:b372877772 "2"^^ . _:b372877921 . _:b372877775 "2"^^ . _:b372877774 "2"^^ . _:b372877769 "2"^^ . . _:b372877820 . _:b372877768 "2"^^ . . _:b372877771 "2"^^ . _:b372877526 . _:b372877770 "2"^^ . . . _:b372877781 "2"^^ . _:b372877780 "2"^^ . _:b372877783 "2"^^ . _:b372877782 "2"^^ . _:b372877713 . _:b372877777 "2"^^ . _:b3291420 "Seizure-induced synaptogenesis is not associated with pruning but with an increase in spine number (Suzuki et al., 1997; Isokawa, >>2000<<) and/or size (Represa et al., 1993)." . . . _:b372877776 "2"^^ . _:b372877779 "2"^^ . _:b372877716 . _:b372877778 "2"^^ . _:b372877789 "2"^^ . _:b372877922 . _:b372877788 "2"^^ . _:b372877791 "2"^^ . . _:b372877438 . _:b372877790 "2"^^ . _:b3291408 "Interestingly, Oray et al. (>>2004<<) have previously demonstrated that degradation of laminin (a principal component of brain ECM) by tissue plasminogen activator (tPA) directly impacts the dynamics of dendritic spines." . _:b372877881 . _:b372877996 . _:b372877309 . _:b372877785 "2"^^ . _:b372877712 . _:b372877784 "2"^^ . . . _:b372877338 . _:b372877787 "2"^^ . . . _:b372877957 . _:b372877786 "2"^^ . . . _:b372877691 . _:b372877797 "2"^^ . _:b372877318 . _:b372877628 . _:b372877796 "2"^^ . _:b372877799 "2"^^ . _:b3291359 . _:b372877798 "2"^^ . _:b372877776 . _:b3291367 "Using an unbiased counting frame (Gundersen, >>1978<<), at each time point we estimated the mean number of colocalizing objects per unit area of the tissue, the ratio of the number of colocalizing objects to the number of all MMP-9\u2013immunoreactive objects, and the mean fluorescence intensity" . _:b372877793 "2"^^ . _:b372877475 . . _:b372877792 "2"^^ . _:b3291405 "It is of interest in this regard that MMP-9 appears to be involved specifically in the late phase of long-term potentiation (Nagy et al., 2006; Okulski et al., >>2007<<). It is possible that the failure of MMP-9\u2013deficient neurons to develop long-lasting potentiation reflected their inability to liberate spines from the milieu of pericellular matrix and cell adhesion proteins, thus curbing their expansion." . _:b372877795 "2"^^ . _:b372877637 . _:b372877794 "2"^^ . _:b372877805 "2"^^ . _:b372877446 . _:b372877804 "2"^^ . _:b372877726 . . _:b372877807 "2"^^ . _:b372877806 "2"^^ . _:b3291364 . _:b372877989 . _:b3291396 . _:b372877801 "2"^^ . _:b372877390 . . _:b372877800 "2"^^ . _:b372877803 "2"^^ . _:b372877809 . . _:b372877802 "2"^^ . _:b372877813 "2"^^ . _:b3291361 . _:b372877812 "2"^^ . . . _:b372877815 "2"^^ . _:b372877814 "2"^^ . _:b372877809 "2"^^ . _:b3291373 . . _:b372877808 "2"^^ . _:b372877445 . _:b372877819 . _:b372877380 . _:b372877811 "2"^^ . _:b372877711 . . _:b372877810 "2"^^ . _:b372877729 . _:b372877821 "2"^^ . . . . _:b372877820 "2"^^ . . _:b372877823 "2"^^ . _:b3291371 "The statistical evaluation of the labelling was performed using the \u03C72 test and observed and expected gold counts over the given compartments (Mayhew et al., >>2003<<)." . . . _:b372877822 "2"^^ . _:b3291380 . _:b372877817 "2"^^ . _:b3291381 . . . _:b372877587 . _:b372877816 "2"^^ . _:b372877819 "2"^^ . . _:b372877675 . _:b372877818 "2"^^ . . . _:b3291344 "(Ben-Ari, 2001), we decided to examine the potential pathogenic role of MMP-9 in two distinct animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling\u2013induced epilepsy (for review see Morimoto et al., >>2004<<)." . . _:b3291415 "Notably, pro\u2013brain-derived neurotrophic factor is an MMP substrate as well (Sternlicht and Werb, >>2001<<). Finally, similar to serine proteinases (Fernandez-Monreal et al., 2004; Kvajo et al., 2004), a proteolytic action of MMP-9 could be directly involved in some aspects of signal transmission (Michaluk and Kaczmarek, 2007)." . . _:b372877598 . . . _:b372877846 . . _:b372877523 . . _:b372877664 . _:b372877545 . . . . _:b3291407 . _:b372877661 . _:b372877678 . . _:b372877339 . . . . _:b3291338 . . . _:b372877393 . _:b3291346 "Instead of dying, the granule neurons of the DG undergo a sequence of plastic phenomena, including pruning of dendritic spines (Suzuki et al., >>1997<<) and axonal sprouting that involves ingrowth of mossy fibers (granule cell axons) into their parent dendritic field to make recurrent excitatory connections (Sutula et al., 1998)." . . . _:b372877374 . _:b372877855 . _:b3291337 "In the adult brain, MMPs have repeatedly been implicated in various pathologies, including acute and chronic neurodegeneration (e.g., in ischemia, trauma, and Alzheimer's disease), inflammation, and cancer (for review see Yong, >>2005<<). Recent studies also suggest that MMP-9 plays an important role in synaptic plasticity, learning, and memory (Szklarczyk et al., 2002; Meighan et al., 2006; Nagy et al., 2006; Okulski et al., 2007; Tian et al., 2007)." . . _:b372877370 . _:b3291349 . . . _:b372877648 . _:b372877866 . . . . . . _:b372877663 . _:b372877987 . . _:b372877775 . . . _:b3291428 . . _:b3291355 . . _:b3291345 . . . _:b372877369 . _:b372877419 . _:b372877302 . . . _:b372877396 . _:b372878032 . _:b372877465 . _:b372877978 . . _:b372877480 . . _:b372877484 . . . _:b372877803 . . _:b372877822 . _:b372877422 . . . . _:b372877931 . . _:b372877848 . _:b372877473 . _:b372877883 . _:b3291411 "Outside the brain, members of these families are known to function as either MMP substrates or receptors (Sternlicht and Werb, >>2001<<). The role of integrins in MMP-9\u2013mediated synaptic plasticity is strongly supported by the finding that MMP-9\u2013mediated long-term potentiation depends on intact integrin function (Nagy et al., 2006). Finally, as found by Tian et al." . _:b372877481 . _:b3291398 . _:b372877406 . . . _:b372877779 . . . _:b3291417 "Finally, similar to serine proteinases (Fernandez-Monreal et al., 2004; Kvajo et al., >>2004<<), a proteolytic action of MMP-9 could be directly involved in some aspects of signal transmission (Michaluk and Kaczmarek, 2007)." . _:b372877799 . _:b3291426 "These are mainly serine proteinases, such as tPA, neuropsin, neurotrypsin, and possibly also thrombin (for review see Shiosaka, >>2004<<). Among MMPs, only MMP-7 and MMP-24 have been added to this group so far (Bilousova et al., 2006; Monea et al., 2006; for review see Ethell and Ethell, 2007). Notably, all these enzymes appear to be involved in some aspects of synaptic" . _:b372877377 . . _:b372877771 . . _:b372877556 . _:b372877839 . _:b372877965 . _:b372877983 . _:b372877429 . . . . . _:b3291391 "In a seminal study by Nedivi et al. (>>1993<<), TIMP1, an endogenous inhibitor of MMPs, was listed among several genes that were found to be up-regulated by kainate treatment specifically in the DG." . . _:b3291373 "The assay was performed according to Szklarczyk et al. (>>2002<<), using gelatin\u2013Sepharose 4B (GE Healthcare) and 8% polyacrylamide gel containing 5 mg/ml of gelatin (Loba Feinchemie) for enzyme purification and detection, respectively." . _:b372878036 . . _:b372877830 . _:b372877699 . _:b372877401 . _:b372877813 . _:b372878004 . . . . _:b372877502 . _:b372877334 . . . . . _:b372877383 . _:b372877760 . . . . _:b372877359 . _:b3291383 . _:b372877630 . . _:b372877569 . . . _:b372878028 . . . . . . _:b372877395 . _:b3291421 "cannot exclude the possibility that under some conditions, e.g. during sprouting and synaptogenesis, MMP-9 acts on the presynaptic domain, including axonal growth cones, as suggested by some cell culture studies (Shubayev and Myers, >>2004<<). Finally, it is also possible that MMP-9 exerts its influence on synaptogenesis after being released from glial cells." . _:b3291351 "associated with overt neurodegeneration, yet it induces excessive sprouting of mossy fibers and synaptogenesis, mainly within the mossy fibers' normal terminal field, i.e., at the CA3 pyramidal cells' dendrites (Chen and Strickland, >>1997<<)." . . _:b372877718 . _:b3291385 . _:b372877483 . _:b3291394 . . _:b3291413 "Finally, as found by Tian et al. (>>2007<<), ICAM-5 is an MMP-9 substrate involved directly in spine dynamics." . _:b372877521 . _:b372877331 . . _:b372877550 . _:b372877510 . _:b372877295 "28"^^ . . . _:b372877415 . _:b372877792 . . _:b3291393 "up-regulation, we found that kainate also caused a very prominent increase in neuronal MMP-9 that followed a similar spatiotemporal pattern and occurred at the levels of both gene expression and enzymatic activity (Szklarczyk et al., >>2002<<). Although there is evidence that excitation-driven MMP-9 activation can be deleterious to neurons (Jourquin et al., 2003), this cannot apply to DG granule cells, which are known to survive even the very intense kainate-evoked status" . _:b372877294 "30"^^ . _:b372877299 "21"^^ . _:b372877296 "26"^^ . . _:b372877297 "25"^^ . _:b372877298 "21"^^ . . _:b372877300 "19"^^ . _:b372877301 "16"^^ . . . _:b372877302 "16"^^ . . _:b3291353 "materials and methods" . _:b372877303 "16"^^ . . _:b372877519 . _:b3291366 . . _:b372877304 "16"^^ . _:b372877305 "16"^^ . . _:b372877428 . _:b372877306 "15"^^ . . _:b372877307 "15"^^ . _:b372877901 . _:b372877308 "15"^^ . _:b372877309 "14"^^ . _:b372877655 . _:b372877310 "14"^^ . _:b372877311 "14"^^ . _:b372877992 . _:b372877815 . _:b3291363 "Both antibodies recognize active and latent forms of MMP-9 (Betsuyaku et al., >>2000<<; Szklarczyk et al., 2002)." . _:b372877542 . _:b372877949 . _:b372877443 . . _:b372877889 . _:b372877457 . _:b372877348 . _:b372877555 . . _:b3291370 . _:b372877735 . . . _:b3291368 . . . _:b3291369 . . . . _:b3291347 . _:b372877653 . _:b372877787 . _:b3291348 "The sprouting is believed to underlie spontaneous seizures that occur in kainate-treated animals after some latency period (for review see Morimoto et al., >>2004<<). It is of interest to note that kainate strongly up-regulates MMP-9 in the DG (Szklarczyk et al., 2002)." . _:b372877462 . _:b372877895 . _:b3291362 . _:b372877315 . _:b3291417 . _:b372877736 . _:b3291363 . _:b3291403 . _:b3291377 "results" . . . _:b372877923 . _:b3291354 "Werb, University of California, San Francisco, San Francisco, CA; Vu et al., >>1998<<), all according to the rules established by the Ethical Committee on Animal Research of the Nencki Institute, based on national laws that are in full agreement with the European Union directive on animal experimentation." . _:b372877489 . . _:b372877305 . . _:b372877911 . . . _:b372877476 . . . _:b372877447 . _:b372878008 . _:b372877566 . _:b372877898 . . _:b372877656 . _:b372877436 . . . _:b3291416 . _:b372877958 . . . . . . . _:b372877772 . _:b372877448 . . . _:b372877532 . _:b372877695 . _:b372877615 . . _:b372877455 . _:b372877599 . . _:b3291430 "Besides being engaged in normal processes, tPA and neuropsin were implicated in the pathogenesis of epilepsy (Wu et al., 2000; for review see Shiosaka, >>2004<<). It remains to be determined if, and how, these enzymes interact with one another in health and disease, e.g., whether presynaptic tPA can function as an activator of postsynaptic MMP-9." . . _:b372877539 . . _:b372877300 . . _:b3291406 "This concept would be in agreement with recent findings (Tian et al., >>2007<<) suggesting that cleavage of a dendritic spine adhesion molecule, intercellular adhesion molecule (ICAM) 5 (telencephalin), by MMP-9 is required for activity-dependent spine enlargement." . _:b372877842 . _:b372877753 . _:b372877640 . . _:b372877355 . . _:b372877572 . _:b372877416 . _:b372877700 . _:b372877299 . . . . . _:b372877829 "2"^^ . _:b3291351 . _:b372877828 "2"^^ . . _:b372877831 "2"^^ . _:b372877830 "2"^^ . . _:b372877825 "2"^^ . . _:b372877824 "2"^^ . _:b372877478 . _:b372877827 "2"^^ . . . _:b372877826 "2"^^ . _:b372877959 . _:b372877837 "2"^^ . . _:b372877836 "2"^^ . . _:b372877839 "2"^^ . _:b372877683 . . _:b3291335 "It is defined by recurrent spontaneous seizures that may be generated by synchronous firing of a localized group of neurons, the so-called epileptic foci (Engel, 1996; Pitkanen and Sutula, >>2002<<). Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. It is characterized by the presence of epileptic foci located within the hippocampal formation, amygdala, or temporal neocortex. Unfortunately, in as many as" . _:b372877838 "2"^^ . . . _:b3291372 . _:b372877833 "2"^^ . . _:b372877832 "2"^^ . . _:b372877835 "2"^^ . . . . _:b372877834 "2"^^ . _:b372877845 "2"^^ . . _:b372877844 "2"^^ . _:b372877847 "2"^^ . . . _:b372877846 "2"^^ . _:b372877841 "2"^^ . . _:b372877840 "2"^^ . . _:b372877782 . _:b372877586 . _:b372877843 "2"^^ . _:b372877546 . . _:b372877842 "2"^^ . _:b372877730 . _:b3291391 . . . _:b372877853 "2"^^ . _:b372877733 . . _:b372877852 "2"^^ . _:b372877855 "2"^^ . _:b372877854 "2"^^ . _:b372877583 . . . _:b372877849 "2"^^ . . . _:b372877851 . _:b372877848 "2"^^ . _:b372877838 . _:b372877562 . _:b372877851 "2"^^ . _:b372877731 . _:b372877850 "2"^^ . _:b372877861 "2"^^ . . _:b372877896 . _:b372877860 "2"^^ . . . _:b372877325 . _:b372877863 "2"^^ . . . . _:b372877365 . _:b372877862 "2"^^ . . _:b372877857 "2"^^ . _:b3291343 "As epileptogenic plasticity involves extensive nervous tissue remodeling (Ben-Ari, >>2001<<), we decided to examine the potential pathogenic role of MMP-9 in two distinct animal models of TLE:" . _:b372877948 . . _:b372877856 "2"^^ . _:b372877845 . _:b372877859 "2"^^ . _:b372877692 . _:b3291369 "Preembedding technique was used according to Boeckers et al. (>>1999<<). In brief, the brains were perfusion fixed with 4% PFA (plus 0.1% gluteraldehyde in the case of anti\u2013MMP-9) and immunostained free floating just as for light microscopy, except that repeated freezing thawing was applied at the" . . . _:b372877858 "2"^^ . _:b372877966 . _:b372877869 "2"^^ . _:b372877347 . _:b372877841 . _:b372877868 "2"^^ . _:b372877909 . _:b372877871 "2"^^ . _:b372877870 "2"^^ . _:b372877865 "2"^^ . . _:b372877864 "2"^^ . _:b372877867 "2"^^ . _:b372877866 "2"^^ . . _:b372877877 "2"^^ . . _:b372877705 . _:b372877876 "2"^^ . _:b372877879 "2"^^ . _:b372877878 "2"^^ . _:b372877704 . _:b372877873 "2"^^ . . _:b3291366 "Light microscopic immunocytochemistry was performed essentially according to Boeckers et al. (>>1999<<) in either 50-\u03BCm-thick free-floating sections of frozen tissues or 4-\u03BCm-thick paraffin sections." . . . _:b372877872 "2"^^ . _:b372877773 . _:b372877875 "2"^^ . _:b372877874 "2"^^ . _:b372877482 . _:b372877885 "2"^^ . _:b372877884 "2"^^ . _:b372877824 . _:b3291365 "Sprouting mossy fiber terminals were visualized using a rabbit anti-synaptoporin antiserum (Synaptic Systems GmbH; Singec et al., >>2002<<) diluted at 1:" . _:b372877887 "2"^^ . _:b372877886 "2"^^ . _:b372877916 . _:b372877568 . _:b372877881 "2"^^ . _:b372877880 "2"^^ . _:b372878023 . . . _:b372877883 "2"^^ . _:b3291374 "We first used established techniques of in situ zymography in which a quenched fluorescent substrate (DQ gelatin) is applied to fresh-frozen tissue sections (Oh et al., >>1999<<; Jourquin et al., 2003). This approach, however, was totally unsatisfactory because tissue integrity was very poorly preserved, which was evident at the high magnifications required to visualize individual dendrites." . _:b372877882 "2"^^ . . _:b372877893 "2"^^ . _:b372877892 "2"^^ . _:b372877895 "2"^^ . . _:b372877778 . _:b372877353 . . _:b372877894 "2"^^ . _:b372877889 "2"^^ . _:b372877888 "2"^^ . _:b372877891 "2"^^ . _:b372877589 . . _:b372877890 "2"^^ . _:b372877926 . _:b372877901 "2"^^ . _:b372877900 "2"^^ . . _:b372877743 . _:b372877903 "2"^^ . . _:b372877902 "2"^^ . . _:b372877402 . _:b372877897 "2"^^ . . _:b372877896 "2"^^ . _:b372877899 "2"^^ . _:b372877313 . _:b372877296 . _:b372877898 "2"^^ . _:b372877297 . _:b372877298 . _:b372877299 . _:b3291386 . _:b372877300 . _:b372877909 "2"^^ . _:b372877301 . _:b372877302 . _:b372877303 . _:b372877304 . _:b372877917 . _:b372877908 "2"^^ . . _:b372877305 . _:b372877306 . _:b372877307 . _:b372877308 . _:b372877911 "2"^^ . _:b372877309 . _:b372877499 . _:b372877310 . _:b3291414 "This would be similar to the action of tPA toward pro\u2013brain-derived neurotrophic factor (Pang et al., >>2004<<). Notably, pro\u2013brain-derived neurotrophic factor is an MMP substrate as well (Sternlicht and Werb, 2001). Finally, similar to serine proteinases (Fernandez-Monreal et al., 2004; Kvajo et al., 2004), a proteolytic action of MMP-9 could be" . _:b372877703 . _:b372877311 . _:b372877474 . _:b372877910 "2"^^ . "PMC0" . _:b372877905 "2"^^ . _:b372877941 . . . . _:b372877904 "2"^^ . . _:b372877946 . _:b372877907 "2"^^ . _:b372877294 . _:b372877295 . _:b372877360 . _:b372877906 "2"^^ . . _:b372877917 "2"^^ . _:b3291384 "Epileptogenesis in the kainate-treated hippocampus begins within \u223C1 wk after the insult when sprouting mossy fibers start to make recurrent synapses with granule cell dendrites (Suzuki et al., >>1997<<; Sutula et al., 1998; Ben-Ari, 2001)." . . _:b3291396 . _:b372877916 "2"^^ . . _:b3291397 . _:b372877919 "2"^^ . _:b3291398 . _:b372877918 "2"^^ . _:b3291399 . _:b372877913 "2"^^ . . _:b3291359 "In the case of picrotoxin, the compound was present in culture medium at concentration of 100 \u03BCM throughout the whole culturing period (Koyama et al., >>2004<<). MMP-9 inhibition was achieved by growing the cultures in the presence of the specific MMP-9 inhibitor S24994 (Hanessian et al., 2001) at a 100-nM concentration. The inhibitor was either present from the beginning (picrotoxin experiment)" . _:b3291392 . _:b372877912 "2"^^ . _:b3291393 . . _:b372877915 "2"^^ . _:b372877617 . . _:b3291394 . _:b372877914 "2"^^ . _:b372877641 . _:b3291395 . _:b372877404 . _:b3291426 . _:b3291392 . _:b372877925 "2"^^ . _:b372877323 . _:b3291404 . _:b372877924 "2"^^ . _:b3291405 . _:b372877927 "2"^^ . . _:b3291343 . _:b3291406 . _:b372877392 . _:b372877926 "2"^^ . _:b3291407 . _:b372877921 "2"^^ . _:b3291430 . _:b372877759 . . _:b3291400 . _:b372877920 "2"^^ . . . _:b3291401 . _:b372877923 "2"^^ . _:b372877859 . _:b3291402 . _:b372877922 "2"^^ . _:b3291403 . _:b372877933 "2"^^ . _:b3291335 . . . _:b3291412 . _:b372877932 "2"^^ . . _:b372877666 . . _:b3291413 . _:b372877935 "2"^^ . . _:b3291418 . _:b3291414 . . _:b372877934 "2"^^ . _:b3291415 . . _:b372877929 "2"^^ . . _:b3291408 . _:b372877928 "2"^^ . _:b372877840 . _:b3291409 . _:b372877931 "2"^^ . _:b372877622 . _:b372877349 . _:b3291410 . _:b372877930 "2"^^ . _:b372877985 . _:b3291411 . _:b372877941 "2"^^ . _:b3291420 . _:b372877681 . _:b372877940 "2"^^ . _:b372877450 . _:b3291421 . _:b3291339 "Recent studies also suggest that MMP-9 plays an important role in synaptic plasticity, learning, and memory (Szklarczyk et al., 2002; Meighan et al., >>2006<<; Nagy et al., 2006; Okulski et al., 2007; Tian et al., 2007)." . _:b372877943 "2"^^ . . _:b3291422 . _:b372877942 "2"^^ . _:b3291423 . _:b372877341 . _:b372877937 "2"^^ . _:b372877885 . . _:b3291416 . _:b372877936 "2"^^ . . _:b3291417 . _:b372877685 . _:b372877939 "2"^^ . _:b372877977 . _:b372877944 . _:b3291418 . _:b372877938 "2"^^ . . . _:b3291419 . _:b372877949 "2"^^ . . . _:b3291428 . _:b372877948 "2"^^ . . _:b3291429 . . _:b372877951 "2"^^ . _:b372877320 . . _:b372877342 . _:b3291430 . _:b372877950 "2"^^ . _:b3291431 . _:b372877945 "2"^^ . _:b3291424 . _:b372877944 "2"^^ . _:b3291425 . _:b372877947 "2"^^ . _:b3291338 "Recent studies also suggest that MMP-9 plays an important role in synaptic plasticity, learning, and memory (Szklarczyk et al., >>2002<<; Meighan et al., 2006; Nagy et al., 2006; Okulski et al., 2007; Tian et al., 2007)." . _:b372877575 . _:b3291426 . _:b372877946 "2"^^ . . _:b372877800 . _:b3291427 . _:b372877957 "2"^^ . _:b372877874 . _:b372877956 "2"^^ . _:b372877959 "2"^^ . _:b3291381 "We showed previously that kainate-induced up-regulation of the bulk gelatinolytic activity peaks at this time point (Szklarczyk et al., >>2002<<)." . . _:b372877958 "2"^^ . _:b3291337 . _:b372877970 . _:b372877953 "2"^^ . . _:b372877766 . _:b372877505 . _:b372877952 "2"^^ . _:b372877821 . _:b3291390 "discussion" . _:b372877991 . . _:b372877955 "2"^^ . _:b372877368 . _:b372877954 "2"^^ . _:b372877965 "2"^^ . _:b372877826 . _:b372877964 "2"^^ . _:b372877967 "2"^^ . . _:b372877391 . _:b372877988 . _:b372877966 "2"^^ . _:b372877961 "2"^^ . . _:b372877384 . _:b372877960 "2"^^ . . _:b372877808 . _:b3291347 "including pruning of dendritic spines (Suzuki et al., 1997) and axonal sprouting that involves ingrowth of mossy fibers (granule cell axons) into their parent dendritic field to make recurrent excitatory connections (Sutula et al., >>1998<<). The sprouting is believed to underlie spontaneous seizures that occur in kainate-treated animals after some latency period (for review see Morimoto et al., 2004)." . _:b372877534 . _:b372877963 "2"^^ . _:b372877829 . . _:b372877619 . _:b3291361 "; Szklarczyk et al., >>2002<<) and an antibody raised against the epitope comprising the catalytic domain of the mouse enzyme (gift from R." . _:b372877962 "2"^^ . . _:b372877828 . _:b372877879 . . _:b372877973 "2"^^ . _:b372877831 . . . _:b372877972 "2"^^ . . _:b372877830 . _:b372877975 "2"^^ . _:b372877408 . _:b372877825 . _:b372877974 "2"^^ . . _:b372877824 . _:b372877969 "2"^^ . _:b372877827 . _:b372877968 "2"^^ . _:b372877826 . _:b372877790 . . _:b372877971 "2"^^ . _:b372877837 . _:b372877970 "2"^^ . _:b372877453 . _:b372877836 . . _:b372877981 "2"^^ . _:b372877839 . _:b372877980 "2"^^ . _:b372877838 . _:b372877983 "2"^^ . _:b372877833 . _:b372877982 "2"^^ . . _:b372877832 . _:b372877466 . _:b372877977 "2"^^ . _:b372877835 . _:b372877976 "2"^^ . _:b372877834 . _:b372877979 "2"^^ . _:b372877593 . _:b372877845 . _:b372877929 . _:b372877978 "2"^^ . _:b372877844 . _:b372877533 . _:b372877989 "2"^^ . _:b372877847 . . _:b372877988 "2"^^ . _:b372877846 . _:b372877991 "2"^^ . _:b372877841 . _:b372877990 "2"^^ . _:b372877840 . _:b372877721 . _:b372877985 "2"^^ . . _:b372877843 . . _:b372877984 "2"^^ . _:b372877842 . . _:b372877987 "2"^^ . _:b372877853 . _:b372877986 "2"^^ . _:b372877852 . _:b372877997 "2"^^ . . _:b372877855 . _:b372877398 . _:b372877996 "2"^^ . _:b372877317 . _:b372877854 . _:b372877999 "2"^^ . _:b372877849 . _:b372877998 "2"^^ . . _:b372877848 . . _:b372877387 . . _:b372877500 . _:b372877993 "2"^^ . . . _:b372877851 . _:b372877626 . _:b372877992 "2"^^ . _:b372877665 . _:b372877850 . . _:b372877995 "2"^^ . . _:b372877861 . . . _:b372877994 "2"^^ . _:b3291408 . _:b372877860 . _:b372877644 . _:b372878005 "2"^^ . _:b372877373 . . _:b372877986 . _:b372877863 . _:b372878004 "2"^^ . . _:b372877862 . _:b372878007 "2"^^ . . . _:b372877857 . _:b372878006 "2"^^ . _:b372877856 . . _:b372878001 "2"^^ . _:b372877294 . _:b372877859 . . _:b372878000 "2"^^ . _:b372877858 . _:b372878003 "2"^^ . . _:b372877869 . _:b372877783 . _:b372877947 . _:b372877854 . _:b372878002 "2"^^ . _:b372877732 . _:b372877868 . _:b372878013 "2"^^ . . _:b372877871 . _:b372878012 "2"^^ . _:b372877870 . _:b372878015 "2"^^ . _:b372877865 . _:b372878014 "2"^^ . . _:b372877864 . _:b372878009 "2"^^ . . _:b372877867 . _:b372877508 . . _:b372878008 "2"^^ . . _:b372877866 . _:b3291379 . _:b372878011 "2"^^ . _:b372877877 . _:b372877940 . _:b372878010 "2"^^ . _:b372877876 . _:b3291390 _:b3291420 . _:b3291390 _:b3291421 . _:b372878021 "2"^^ . _:b372877580 . _:b372877490 . _:b3291390 _:b3291422 . . _:b372877879 . _:b3291390 _:b3291423 . _:b3291390 _:b3291416 . _:b3291390 _:b3291417 . _:b372878020 "2"^^ . _:b3291390 _:b3291418 . . _:b372877878 . _:b3291390 _:b3291419 . _:b3291390 _:b3291412 . _:b3291390 _:b3291413 . _:b372878023 "2"^^ . _:b3291390 _:b3291414 . _:b3291390 _:b3291415 . _:b372877873 . _:b3291390 _:b3291408 . _:b3291390 _:b3291409 . _:b372878022 "2"^^ . _:b3291390 _:b3291410 . _:b3291390 _:b3291411 . _:b372877872 . _:b3291390 _:b3291404 . _:b3291390 _:b3291405 . _:b372878017 "2"^^ . . _:b3291390 _:b3291406 . _:b372877658 . _:b372877875 . _:b3291390 _:b3291407 . _:b3291390 _:b3291400 . _:b3291390 _:b3291401 . _:b372878016 "2"^^ . _:b3291390 _:b3291402 . . _:b3291390 _:b3291403 . _:b372877874 . _:b3291390 _:b3291396 . _:b3291390 _:b3291397 . _:b372878019 "2"^^ . _:b3291390 _:b3291398 . _:b3291390 _:b3291399 . _:b372877885 . _:b3291390 _:b3291392 . . _:b3291390 _:b3291393 . _:b372878018 "2"^^ . . _:b3291410 "Cadherins and integrins are two major families of synaptic adhesion proteins that have been strongly implicated in spine physiology (Benson et al., >>2000<<). Outside the brain, members of these families are known to function as either MMP substrates or receptors (Sternlicht and Werb, 2001). The role of integrins in MMP-9\u2013mediated synaptic plasticity is strongly supported by the finding that" . . _:b3291390 _:b3291394 . _:b3291390 _:b3291395 . _:b372877884 . . . _:b372878029 "2"^^ . _:b372877887 . _:b372877512 . _:b372878028 "2"^^ . _:b372877886 . _:b372878031 "2"^^ . . _:b372877881 . . _:b372878030 "2"^^ . _:b372877880 . _:b372878025 "2"^^ . _:b372877883 . _:b372878024 "2"^^ . . . _:b372877882 . _:b3291390 _:b3291428 . _:b3291390 _:b3291429 . _:b372878027 "2"^^ . _:b3291390 _:b3291430 . _:b3291390 _:b3291431 . _:b372877893 . _:b372877516 . _:b3291390 _:b3291424 . _:b3291390 _:b3291425 . _:b372878026 "2"^^ . . _:b3291390 _:b3291426 . _:b372877432 . _:b3291390 _:b3291427 . _:b372877892 . _:b372877643 . _:b372878037 "2"^^ . _:b372877895 . _:b372878036 "2"^^ . _:b372877894 . . . . _:b372877889 . _:b372877888 . _:b372877634 . _:b372878033 "2"^^ . _:b372877440 . _:b372877891 . _:b372878032 "2"^^ . _:b372877890 . . _:b372878035 "2"^^ . _:b372877693 . _:b372877901 . _:b372878034 "2"^^ . _:b372877900 . . _:b372877903 . . _:b372877458 . _:b372877902 . . _:b372877897 . . _:b372877434 . _:b372877896 . _:b3291357 "Mice received intraperitoneal injections of 30\u201340 mg/kg PT every other day consecutively for 6 wk (De Sarro et al., >>2004<<). Behavioral seizures were scored according to a modified scale of Racine:" . _:b372877899 . _:b372877755 . _:b372877898 . _:b372877316 . . _:b372877763 . _:b372877909 . . _:b372877677 . _:b372877908 . _:b372877911 . _:b372877603 . _:b372877761 . _:b372877910 . . _:b372877905 . . _:b372877904 . _:b372877715 . _:b372877907 . _:b372877918 . . . . _:b372877906 . _:b372877541 . _:b372877917 . _:b372877552 . _:b372877916 . _:b372877407 . _:b372877919 . . _:b372877918 . _:b372877882 . _:b372878034 . _:b372877399 . _:b372877913 . _:b372877912 . . _:b372877915 . _:b372877814 . _:b372877914 . . . _:b372877925 . . _:b372877372 . _:b372877694 . _:b372877969 . _:b372877924 . _:b372877449 . _:b372877927 . _:b372877926 . _:b372877375 . _:b372877921 . _:b372877754 . _:b372877920 . . _:b372877491 . _:b372877923 . _:b372877652 . _:b372877864 . _:b372877296 . _:b372877922 . . _:b372877366 . . _:b372877933 . _:b372877932 . . _:b372877935 . _:b372877934 . . _:b372877929 . _:b3291395 . _:b3291388 "In contrast, when a specific MMP-9 inhibitor, S24994 (Hanessian et al., >>2001<<), was applied after kainate, there was virtually no synaptoporin immunolabeling and, thus, apparently no sprouting (Fig." . . . _:b372877706 . _:b372877928 . . _:b372877931 . . _:b372877507 . . _:b372877930 . . _:b372877941 . . _:b372877940 . _:b372877943 . _:b372878001 . _:b372877942 . _:b372877804 . . _:b372877937 . _:b372877936 . _:b372877939 . _:b372877938 . _:b372877949 . _:b3291354 . . _:b372877948 . _:b372877934 . . . . _:b372877951 . _:b3291334 _:b3291352 . _:b372877950 . . _:b3291334 _:b3291348 . _:b3291334 _:b3291349 . _:b3291334 _:b3291350 . _:b3291334 _:b3291351 . _:b372877945 . _:b3291334 _:b3291344 . _:b372877748 . _:b3291334 _:b3291345 . _:b3291334 _:b3291346 . . _:b3291334 _:b3291347 . _:b372877944 . _:b3291334 _:b3291340 . _:b3291334 _:b3291341 . . _:b3291334 _:b3291342 . _:b3291334 _:b3291343 . _:b372877947 . _:b3291334 _:b3291336 . _:b3291334 _:b3291337 . _:b3291334 _:b3291338 . _:b3291334 _:b3291339 . _:b372877946 . _:b372877394 . _:b3291334 _:b3291335 . _:b372877957 . _:b372877932 . . _:b3291341 . _:b372877956 . . _:b372877959 . _:b372877958 . . _:b372877410 . _:b372877554 . _:b372877953 . _:b372877595 . . _:b372877952 . _:b372877437 . _:b372877861 . _:b372877431 . . _:b372877937 . _:b372877955 . . _:b372877645 . _:b372877954 . _:b3291353 _:b3291354 . _:b3291353 _:b3291355 . _:b372877965 . _:b3291353 _:b3291356 . _:b372877764 . _:b3291353 _:b3291357 . _:b3291353 _:b3291358 . _:b3291353 _:b3291359 . _:b372877964 . . _:b3291353 _:b3291360 . _:b372877722 . _:b3291353 _:b3291361 . _:b3291353 _:b3291362 . _:b3291353 _:b3291363 . _:b372877967 . _:b3291353 _:b3291364 . . _:b3291353 _:b3291365 . _:b3291353 _:b3291366 . _:b3291353 _:b3291367 . _:b372877966 . . _:b3291353 _:b3291368 . _:b3291353 _:b3291369 . _:b3291353 _:b3291370 . _:b3291353 _:b3291371 . _:b372877961 . _:b3291353 _:b3291372 . _:b3291353 _:b3291373 . _:b3291353 _:b3291374 . _:b3291353 _:b3291375 . _:b372877960 . _:b3291353 _:b3291376 . . _:b372877963 . _:b372877938 . . _:b372877310 . . _:b372877962 . _:b372877688 . _:b372877973 . _:b372877935 . . . _:b3291422 "Indeed, the presence of MMP-9 in astrocytes (by double labeling with GFAP; Szklarczyk et al., >>2002<<) and in oligodendrocytes under nonstimulated conditions (Oh et al., 1999) has been previously described." . . _:b372877972 . . _:b372877975 . _:b372877477 . _:b372877620 . _:b372877876 . _:b372877974 . _:b372877746 . _:b372877893 . _:b372877969 . . _:b372877464 . _:b372877968 . _:b372877531 . . _:b372877744 . _:b372877971 . . . _:b372877970 . _:b372877425 . _:b372877894 . _:b372877411 . . _:b372877629 . . _:b372877981 . _:b372877501 . _:b372877762 . . . _:b372877980 . _:b372877371 . _:b372877983 . _:b372877357 . _:b372878017 . _:b372877982 . _:b372877977 . _:b372877976 . _:b372877979 . _:b372877978 . _:b372877920 . _:b372877989 . _:b372877988 . . . _:b372877991 . _:b372877990 . _:b372877985 . _:b3291364 "Both antibodies recognize active and latent forms of MMP-9 (Betsuyaku et al., 2000; Szklarczyk et al., >>2002<<). The following mouse marker antibodies were used for double and triple immunofluorescent stainings: anti\u2013MAP-2, a dendritic marker, diluted at 1:200 (Millipore); anti-synaptophysin, a presynaptic marker, diluted at 1:20 (Dako); and" . _:b372877877 . _:b372877984 . _:b3291377 _:b3291378 . _:b3291377 _:b3291379 . _:b372877987 . _:b3291377 _:b3291380 . _:b3291377 _:b3291381 . _:b3291377 _:b3291382 . _:b372877565 . _:b372877986 . _:b3291377 _:b3291383 . . _:b3291377 _:b3291384 . _:b3291377 _:b3291385 . _:b372878006 . _:b3291377 _:b3291386 . . _:b3291377 _:b3291387 . _:b372877997 . _:b3291377 _:b3291388 . _:b3291349 "It is of interest to note that kainate strongly up-regulates MMP-9 in the DG (Szklarczyk et al., >>2002<<)." . _:b3291377 _:b3291389 . . . _:b372877996 . _:b3291390 _:b3291391 . _:b372877999 . _:b372877611 . _:b372877998 . . _:b372877993 . _:b372877992 . _:b372877413 . _:b372877995 . _:b372877689 . _:b3291365 . . _:b372877994 . . _:b372878005 . _:b3291385 "Epileptogenesis in the kainate-treated hippocampus begins within \u223C1 wk after the insult when sprouting mossy fibers start to make recurrent synapses with granule cell dendrites (Suzuki et al., 1997; Sutula et al., >>1998<<; Ben-Ari, 2001)." . _:b3291419 "Seizure-induced synaptogenesis is not associated with pruning but with an increase in spine number (Suzuki et al., >>1997<<; Isokawa, 2000) and/or size (Represa et al., 1993)." . _:b372878004 . _:b372878007 . _:b372877452 . _:b372878006 . _:b372877860 . _:b372878001 . _:b3291412 "The role of integrins in MMP-9\u2013mediated synaptic plasticity is strongly supported by the finding that MMP-9\u2013mediated long-term potentiation depends on intact integrin function (Nagy et al., >>2006<<). Finally, as found by Tian et al. (2007), ICAM-5 is an MMP-9 substrate involved directly in spine dynamics. However, besides the proposed role in structural plasticity, MMP-9 could cleave and thereby activate (or inhibit) other molecules" . . _:b372878000 . _:b372877738 . _:b372878003 . . _:b372878002 . . . _:b372878013 . . . _:b372877335 . _:b372878012 . _:b372878015 . _:b372877850 . _:b372878014 . _:b372877798 . . _:b372878009 . _:b372877548 . _:b372878008 . _:b372877551 . _:b372878011 . . _:b372877361 . _:b372878010 . . _:b372878021 . _:b372878007 . _:b372878020 . . _:b372877751 . _:b372878023 . . . . _:b372878022 . _:b372878017 . _:b372877594 . . . _:b372878016 . . _:b372878019 . _:b372878018 . _:b3291340 "Recent studies also suggest that MMP-9 plays an important role in synaptic plasticity, learning, and memory (Szklarczyk et al., 2002; Meighan et al., 2006; Nagy et al., >>2006<<; Okulski et al., 2007; Tian et al., 2007)." . _:b372877460 . _:b372878029 . _:b372877794 . . _:b372877537 . . _:b372878028 . . . _:b372878031 . . _:b372877559 . _:b372877488 . _:b372878030 . _:b372877544 . _:b372877659 . _:b372878025 . _:b372877806 . . _:b372878024 . . . . _:b372878027 . _:b372877333 . _:b372877793 . . _:b372877430 . _:b372878026 . _:b372877724 . . _:b372878037 . . _:b372878036 . . _:b372877295 . _:b372878033 . _:b372878032 . _:b372878035 . _:b372877581 . _:b372878034 . _:b3291382 "However, it should also be noted that a latent form of MMP-9 has been suggested to have some gelatinolytic activity in vivo (Bannikov et al., >>2002<<)." . . . . . _:b372877867 . . _:b372877522 . . _:b372877472 . _:b372877769 . _:b372877525 . _:b372877298 . _:b372877517 . _:b372877925 . . _:b372877379 . . . _:b372877936 . _:b372877930 . . . . . . _:b3291379 "To avoid any indirect effects of MMP-9 deficiency that could occur in the kainate model because of the well known role of MMP-9 in neuronal death (Jourquin et al., 2003; for review see Yong, >>2005<<), we decided to investigate a chemical kindling model that, in contrast to the kainate model, does not involve neurodegeneration." . _:b3291431 . _:b372877624 . _:b372877529 . _:b3291341 "Recent studies also suggest that MMP-9 plays an important role in synaptic plasticity, learning, and memory (Szklarczyk et al., 2002; Meighan et al., 2006; Nagy et al., 2006; Okulski et al., >>2007<<; Tian et al., 2007)." . . _:b372877304 . . _:b372877354 . _:b372877417 . _:b372877976 . . . _:b372877723 . _:b372878018 . . _:b372877409 . . . _:b372877752 . _:b372877979 . . . _:b372877306 . _:b372877573 . . _:b372877903 . _:b372877572 . _:b372877575 . _:b3291428 "Among MMPs, only MMP-7 and MMP-24 have been added to this group so far (Bilousova et al., 2006; Monea et al., 2006; for review see Ethell and Ethell, >>2007<<). Notably, all these enzymes appear to be involved in some aspects of synaptic plasticity. Besides being engaged in normal processes, tPA and neuropsin were implicated in the pathogenesis of epilepsy (Wu et al., 2000; for review see" . _:b372877574 . . . _:b372877696 . . _:b372877569 . . _:b372877568 . _:b3291339 . _:b372877571 . . _:b372877570 . _:b372877791 . _:b372877456 . . _:b372877581 . _:b372877714 . _:b372877580 . _:b372877578 . _:b372877332 . . _:b372877583 . _:b372877582 . _:b372877577 . _:b372877424 . _:b372877576 . . _:b372877579 . _:b372877578 . _:b372877589 . _:b3291376 "power confocal micrographs of the hippocampal organotypic cultures demonstrating the effect of pharmacological inhibition of MMP-9 on kainate-induced mossy fibers sprouting (in both supra- and infragranular layer [Frotscher et al., >>2000<<]). Online supplemental material is available at http://www.jcb.org/cgi/content/full/jcb." . _:b372877708 . _:b372877906 . _:b3291424 "Furthermore, our ultrastructural immunolocalization, as well as electron microscopic in situ hybridization data (Konopacki et al., >>2007<<), consistently indicates the presence of the enzyme in the tiny astrocytic processes that ensheath the synapses." . _:b372877588 . _:b372877591 . _:b372877880 . . _:b372877590 . . . . _:b3291382 . . _:b372877585 . _:b372877403 . _:b372877584 . _:b372877587 . . _:b372877586 . . _:b372877597 . _:b372877301 . . _:b372877596 . . . _:b372877599 . _:b372877598 . _:b372877593 . . _:b372877592 . _:b372877595 . _:b372877535 . _:b3291384 . _:b372878030 . _:b372878035 . _:b372877621 . _:b372877594 . . _:b3291420 . _:b372877605 . . _:b372877604 . _:b372877607 . _:b372877756 . . _:b372877606 . _:b372877601 . . _:b372877886 . _:b372877600 . _:b372877603 . _:b372877602 . _:b372877765 . _:b3291429 . _:b372877613 . _:b372878025 . . . _:b372877612 . . _:b372878012 . _:b372877615 . _:b372877328 . _:b372877631 . _:b372877614 . _:b3291415 . . _:b372877609 . _:b372877340 . _:b372877608 . _:b372877611 . . _:b372877610 . _:b3291411 . . _:b372877621 . _:b372877620 . _:b3291409 . _:b372877623 . _:b372877622 . . _:b372877780 . . . _:b372877571 . _:b372877617 . . _:b372877669 . . . . _:b372877616 . . . _:b372877619 . . _:b372877618 . . _:b372877629 . _:b372877628 . _:b372877518 . _:b372877631 . _:b372877386 . _:b372877630 . . . _:b372877625 . . . _:b372877624 . _:b372877627 . _:b372877768 . _:b372877626 . _:b372877637 . _:b372877636 . _:b372877520 . . . . _:b372877639 . _:b372877638 . . . . _:b372877960 . _:b372877633 . _:b372877303 . _:b372877514 . _:b3291346 . _:b372877632 . . _:b372877635 . _:b372877847 . _:b372877634 . _:b372877645 . . . _:b372877644 . . _:b372877515 . _:b372877647 . _:b372877646 . _:b372877707 . _:b372877641 . _:b372878019 . _:b372877314 . . _:b372878009 . _:b372877640 . . _:b372877553 . _:b372877643 . _:b372877642 . . _:b372877653 . _:b372877817 . _:b372877652 . _:b3291358 "Cultures of hippocampal slices were prepared essentially according to Jourquin et al. (>>2003<<). In brief, 8\u201310-d-old rat pups were decapitated and the hippocampi were rapidly dissected on a cold plate." . _:b372877558 . . _:b372877655 . _:b372877905 . . . . _:b372877654 . _:b372877649 . _:b372877648 . _:b372877651 . _:b372877650 . _:b372877868 . _:b372877661 . _:b372877423 . . _:b372877660 . _:b372877663 . _:b372877662 . . _:b372877657 . . . _:b372877656 . _:b3291412 . _:b372877560 . _:b372877381 . _:b372877659 . . _:b372877426 . _:b372877887 . _:b372877658 . . . _:b372877669 . . . _:b372877668 . . _:b372877638 . _:b372877671 . . _:b372877670 . _:b372877665 . _:b372877664 . _:b3291404 . . . _:b372877667 . _:b372877687 . _:b372877666 . . . . . . _:b372877677 . _:b372877676 . _:b372877871 . _:b372877679 . _:b372877567 . _:b372877678 . . _:b372877805 . . _:b372877673 . _:b3291397 . . _:b372877625 . _:b372877672 . _:b3291387 "Organotypic hippocampal cultures retain the typical anatomical features of the hippocampal formation, thus providing an excellent model to study the effects of various molecules on hippocampal structure and function (Jourquin et al., >>2003<<). We treated such cultures with either kainate or vehicle solution. The cultures were then allowed to recover for 2 wk, after which they were fixed and immunostained for synaptoporin, a marker of mossy fiber boutons." . _:b372877397 . _:b372877675 . . . _:b372877674 . _:b372877685 . . _:b372877749 . _:b372877684 . _:b3291336 "metalloproteinases (MMPs) form a large family of structurally related zinc-dependent secreted or cell membrane\u2013bound proteinases that are considered to be major executors of ECM remodeling throughout the body (Sternlicht and Werb, >>2001<<) and of pivotal importance in cancer invasion and metastasis." . _:b372877312 "14"^^ . _:b372877319 "11"^^ . . _:b372877687 . _:b372877318 "12"^^ . _:b372877686 . _:b372877317 "12"^^ . _:b372877681 . _:b372877680 . _:b372877316 "13"^^ . _:b372877924 . _:b372877683 . _:b372877315 "13"^^ . . _:b372877682 . _:b372877314 "13"^^ . _:b372877933 . _:b372877693 . _:b372877313 "13"^^ . _:b372877692 . _:b372877496 . _:b372877774 . . _:b372877695 . _:b372877995 . _:b372877326 "9"^^ . _:b372877694 . _:b372877327 "9"^^ . _:b372877728 . _:b372877952 . . . _:b372877689 . . _:b372877324 "10"^^ . _:b372877364 . . _:b3291425 "near consensus that sprouting, even if not absolutely required for the TLE to develop, powerfully stimulates epileptogenesis by generating recurrent excitatory circuits within the hippocampal formation (for review see Morimoto et al., >>2004<<). Thus, we believe that it is the effect on pathological synaptogenesis that underlies the role of MMP-9 in the progression of epilepsy (Fig." . _:b372877688 . _:b372877325 "9"^^ . _:b372877463 . _:b372877609 . _:b372877323 "10"^^ . _:b372877691 . _:b372878002 . _:b372877322 "11"^^ . _:b372877312 . _:b372877690 . _:b3291407 "1 I; Hasbani et al., >>2001<<). Thus, it is possible that MMP-9 facilitates elimination, as well as growth of spines, through a single mechanism, i.e., facilitation of spine remodeling." . _:b372877321 "11"^^ . . . _:b372877701 . . . _:b372877320 "11"^^ . . _:b372877700 . _:b372877334 "8"^^ . _:b372877703 . _:b372877467 . _:b372877335 "8"^^ . _:b372877702 . _:b372877650 . _:b372877332 "8"^^ . _:b372877697 . _:b372877322 . _:b372877333 "8"^^ . _:b372877696 . . _:b372877699 . _:b372877330 "9"^^ . _:b372877816 . _:b372877698 . . _:b372877331 "9"^^ . _:b372877350 . _:b372877709 . _:b372877328 "9"^^ . _:b372877618 . _:b372877708 . _:b372877329 "9"^^ . _:b372877342 "7"^^ . _:b372877711 . _:b372877343 "7"^^ . . _:b372877710 . _:b372877739 . _:b3291416 "Finally, similar to serine proteinases (Fernandez-Monreal et al., >>2004<<; Kvajo et al., 2004), a proteolytic action of MMP-9 could be directly involved in some aspects of signal transmission (Michaluk and Kaczmarek, 2007)." . _:b372877340 "8"^^ . _:b372877705 . _:b3291334 . _:b372877498 . _:b372877341 "8"^^ . _:b372877704 . . _:b3291335 . _:b372877330 . . _:b372877338 "8"^^ . _:b372877707 . _:b372877451 . _:b372877339 "8"^^ . _:b372877706 . . _:b372877336 "8"^^ . _:b372877717 . _:b372877590 . _:b372877337 "8"^^ . _:b372877716 . _:b372877524 . _:b372877350 "7"^^ . . _:b372877719 . _:b3291340 . _:b372877351 "7"^^ . _:b372877718 . _:b3291341 . _:b372877348 "7"^^ . _:b372877713 . . _:b3291342 . _:b372877967 . _:b372877349 "7"^^ . _:b372877712 . _:b3291421 . _:b3291343 . _:b372877346 "7"^^ . _:b372877715 . _:b3291336 . _:b372877872 . _:b372877347 "7"^^ . _:b372877714 . _:b372877834 . . _:b3291337 . _:b372877344 "7"^^ . . _:b372877725 . _:b372878021 . _:b3291338 . _:b372877345 "7"^^ . _:b372877724 . . _:b3291339 . _:b372877358 "6"^^ . . _:b372877727 . . _:b3291348 . _:b372877359 "6"^^ . _:b372877726 . _:b372877890 . _:b372877734 . _:b3291349 . _:b372877356 "6"^^ . _:b372877900 . _:b372877721 . _:b3291350 . _:b372877357 "6"^^ . _:b372877720 . _:b3291351 . _:b372877354 "7"^^ . _:b372877723 . _:b3291344 . _:b372877355 "7"^^ . . _:b372877722 . _:b3291345 . _:b372877352 "7"^^ . _:b372877733 . _:b372877950 . _:b3291346 . _:b372877353 "7"^^ . _:b372877732 . _:b3291347 . _:b372877366 "6"^^ . . . _:b372877735 . _:b3291356 . _:b372877367 "6"^^ . _:b372877734 . _:b3291357 . _:b372877364 "6"^^ . _:b372877729 . . _:b3291358 . . _:b372877365 "6"^^ . _:b372877728 . _:b3291359 . . _:b372877362 "6"^^ . _:b372877731 . _:b3291352 . _:b372877363 "6"^^ . . _:b372877730 . _:b372877360 "6"^^ . _:b3291353 . _:b372877579 . _:b372877741 . _:b3291354 . _:b372877361 "6"^^ . _:b372877740 . . _:b3291355 . _:b372877697 . _:b372877743 . . _:b3291364 . _:b372877837 . _:b372877373 "5"^^ . _:b372877742 . _:b3291365 . . _:b372877372 "6"^^ . _:b372877737 . _:b372877807 . . _:b3291366 . _:b372877375 "5"^^ . . _:b372877736 . _:b372877374 "5"^^ . _:b3291367 . . _:b372877370 "6"^^ . . _:b372877739 . _:b3291360 . _:b372877371 "6"^^ . _:b372877738 . _:b372877781 . _:b3291361 . _:b372877368 "6"^^ . . _:b372877749 . _:b3291372 "Isolation of synaptosomes was performed according to Havik et al. (>>2003<<). In brief, frozen tissue was melted, homogenized in a glass homogenizer, and subjected to a series of centrifugations that yielded P1 (cell debris and nuclei), P2 (crude synaptosomes/mitochondria), P3 (microsomes), and S (cytosol)" . _:b3291362 . _:b372877369 "6"^^ . . _:b372877796 . _:b372877748 . _:b3291363 . . _:b372877751 . _:b372877853 . _:b372877381 "5"^^ . _:b3291372 . . _:b372877750 . _:b372877380 "5"^^ . _:b3291373 . . . _:b372877745 . _:b372877383 "5"^^ . _:b3291374 . . . _:b372877744 . _:b372877382 "5"^^ . _:b3291375 . _:b372877747 . _:b372877377 "5"^^ . _:b3291368 . . . _:b372877746 . _:b372877376 "5"^^ . _:b3291369 . _:b372877757 . _:b372877379 "5"^^ . _:b3291370 . . . _:b372877756 . _:b372877378 "5"^^ . _:b3291371 . . _:b372877759 . _:b372877389 "5"^^ . _:b3291380 . . _:b372877758 . . _:b3291381 . _:b372877388 "5"^^ . _:b372877961 . _:b372877753 . _:b372877391 "5"^^ . _:b3291382 . _:b372877740 . _:b372877752 . _:b372877390 "5"^^ . _:b3291383 . _:b372877584 . _:b372877802 . _:b372877755 . _:b372877385 "5"^^ . _:b3291376 . _:b372877754 . _:b372877384 "5"^^ . _:b3291377 . _:b372877849 . _:b372877765 . _:b372877387 "5"^^ . _:b3291378 . _:b372877719 . _:b372877764 . _:b3291405 . _:b372877386 "5"^^ . _:b3291379 . _:b372877378 . . _:b372877767 . _:b372877397 "5"^^ . _:b3291388 . _:b372877766 . _:b372877396 "5"^^ . _:b3291389 . _:b372877486 . _:b372877761 . _:b372877399 "5"^^ . _:b3291390 . . _:b372877760 . _:b372877398 "5"^^ . _:b3291391 . _:b372877400 . _:b372877982 . _:b372877647 . _:b372877763 . . . _:b372877393 "5"^^ . _:b3291384 . . . . _:b372877762 . . _:b372877392 "5"^^ . _:b3291385 . _:b372877773 . _:b372877395 "5"^^ . _:b3291386 . _:b372877980 . _:b372877557 . _:b372877772 . _:b372877394 "5"^^ . _:b3291387 . . . _:b372877775 . _:b372877405 "5"^^ . . . _:b372877774 . . _:b372877404 "5"^^ . _:b372877769 . _:b372877407 "5"^^ . _:b372877875 . _:b372877768 . _:b372877406 "5"^^ . _:b372877771 . _:b372877401 "5"^^ . _:b372877308 . _:b372877770 . _:b372877400 "5"^^ . _:b372877470 . . _:b372877781 . . _:b372877610 . . _:b372877403 "5"^^ . . _:b372877613 . _:b372877780 . _:b3291395 "evidence that excitation-driven MMP-9 activation can be deleterious to neurons (Jourquin et al., 2003), this cannot apply to DG granule cells, which are known to survive even the very intense kainate-evoked status epilepticus (Sperk, >>1994<<). Thus, we hypothesized that the prolonged MMP-9 up-regulation in the DG after status epilepticus represents an insult-related plastic response." . _:b372877402 "5"^^ . _:b372877783 . _:b372877413 "5"^^ . _:b372877782 . _:b372877412 "5"^^ . _:b372877415 "4"^^ . _:b372877777 . _:b372877981 . _:b3291427 . . _:b372877863 . _:b372877414 "4"^^ . _:b372877776 . _:b372877908 . _:b372877779 . _:b372877409 "5"^^ . _:b372877990 . _:b372877778 . _:b372877408 "5"^^ . _:b372877956 . . _:b372877994 . _:b372877789 . _:b372877616 . _:b372877411 "5"^^ . _:b372877788 . _:b372877410 "5"^^ . _:b372877421 "4"^^ . _:b372877791 . _:b3291406 . _:b372877758 . _:b372877420 "4"^^ . _:b372877790 . . _:b372877423 "4"^^ . _:b372877785 . . . _:b372877422 "4"^^ . _:b372877784 . _:b372877709 . _:b372877612 . _:b372877787 . . _:b372877417 "4"^^ . _:b372877416 "4"^^ . _:b372877786 . _:b372877419 "4"^^ . _:b372877797 . _:b372877424 . _:b372877329 . _:b372877425 . . _:b372877426 . _:b372877796 . _:b372877418 "4"^^ . _:b372877427 . _:b372877428 . _:b372877429 . _:b372877561 . _:b372877430 . _:b372877799 . _:b372877429 "4"^^ . _:b372877431 . _:b372877432 . _:b372877433 . _:b372877836 . . _:b372877434 . _:b372877798 . _:b372877428 "4"^^ . _:b372877670 . _:b372877435 . _:b3291413 . . _:b372877436 . _:b372877737 . _:b372877437 . . _:b372877438 . _:b372877793 . _:b372877431 "4"^^ . _:b372877439 . _:b372877408 . _:b372877409 . _:b372877410 . _:b372877792 . _:b372877430 "4"^^ . _:b372877411 . _:b372877412 . _:b372877968 . _:b372877413 . _:b372877414 . _:b372877795 . _:b372877425 "4"^^ . _:b372877415 . _:b372877416 . . _:b372877417 . _:b372877418 . _:b372877794 . _:b372877424 "4"^^ . _:b372877419 . _:b372877420 . _:b372877421 . . _:b372877422 . _:b372877805 . _:b372877427 "4"^^ . _:b372877423 . _:b372877392 . _:b372877393 . _:b372877394 . _:b372877804 . _:b372877426 "4"^^ . _:b372877395 . _:b372878003 . _:b372877396 . _:b372877397 . _:b372877398 . _:b372877807 . _:b372877437 "4"^^ . _:b372877399 . _:b372877358 . _:b372877400 . _:b372877401 . _:b372877402 . _:b372877806 . . _:b372877436 "4"^^ . _:b372877403 . _:b372877404 . _:b372877540 . _:b372877405 . _:b372877406 . _:b372877801 . _:b372877439 "4"^^ . _:b372877407 . _:b372877376 . _:b372877377 . _:b372877378 . _:b372877800 . . _:b372877438 "4"^^ . _:b372877379 . _:b372877380 . _:b372877381 . _:b372877382 . _:b372877963 . _:b372877803 . _:b372877433 "4"^^ . _:b372877383 . _:b372877785 . _:b372877384 . _:b372877385 . _:b372877386 . _:b372877802 . _:b372877432 "4"^^ . _:b372877387 . _:b372877388 . . _:b372877389 . . _:b372877390 . _:b372877813 . _:b372877435 "4"^^ . _:b372877391 . . _:b372877360 . _:b372877361 . _:b372877362 . _:b372877910 . _:b372877812 . _:b372877434 "4"^^ . _:b372877363 . _:b372877364 . _:b372877365 . _:b372877366 . _:b372877815 . _:b372877445 "4"^^ . _:b372877367 . _:b372877368 . _:b372877369 . _:b372877370 . _:b372877904 . _:b372877814 . . _:b372877444 "4"^^ . _:b372877371 . _:b372877372 . _:b372877373 . _:b372877374 . _:b372877809 . _:b372877447 "4"^^ . _:b372877375 . _:b372877344 . _:b372877345 . _:b372877346 . _:b372877808 . _:b372877741 . _:b372877446 "4"^^ . _:b372877347 . _:b372877348 . _:b372877349 . _:b372877350 . _:b372877811 . _:b372877441 "4"^^ . _:b372877351 . _:b372877352 . _:b372877353 . _:b372877354 . _:b372877902 . _:b372877810 . _:b372877440 "4"^^ . _:b372877355 . _:b372877356 . _:b372877357 . . _:b372877358 . _:b372877831 . _:b372877821 . _:b372877443 "4"^^ . . _:b372877359 . _:b372877328 . _:b372877329 . _:b372877330 . _:b372877820 . _:b372877442 "4"^^ . _:b372877331 . . _:b372877332 . _:b3291357 . _:b372877333 . _:b372877334 . _:b372877823 . _:b372877453 "4"^^ . _:b372877335 . _:b3291336 . _:b372877336 . _:b372877337 . _:b372877338 . _:b372877822 . _:b372877452 "4"^^ . _:b372877339 . _:b372877340 . _:b372877341 . _:b372877342 . _:b372877817 . _:b372877455 "4"^^ . _:b372877343 . _:b3291334 "introduction" . . _:b372877312 . _:b372877313 . _:b372877314 . _:b372877816 . . _:b372877454 "4"^^ . _:b372877315 . _:b3291419 . _:b372877316 . _:b372877317 . _:b372877385 . _:b372877318 . _:b372877819 . _:b372877449 "4"^^ . _:b372877319 . _:b372877320 . _:b372877321 . _:b372877972 . _:b372877322 . _:b372877818 . _:b372877448 "4"^^ . _:b372877323 . _:b372877770 . . _:b372877324 . _:b3291423 . _:b372877325 . _:b372877317 . _:b372877451 "4"^^ . _:b372877326 . _:b372877327 . _:b372877552 . _:b372877553 . _:b372877316 . _:b372877450 "4"^^ . _:b372877554 . _:b372877555 . _:b372878029 . _:b372877556 . _:b372877557 . _:b372877441 . _:b372877461 "4"^^ . _:b372877558 . _:b372877319 . _:b372877559 . _:b372877560 . . _:b372877561 . . _:b372877460 "4"^^ . _:b372877562 . _:b372877318 . _:b372877563 . _:b372877564 . _:b372877565 . _:b372877608 . _:b372877313 . _:b372877833 . . _:b372877463 "4"^^ . _:b372877566 . _:b372877567 . _:b3291352 "mechanisms similar to those operating in kainate- and/or kindling-induced animal epilepsy occur during the course of TLE (albeit in a different time frame), as demonstrated by autopsy studies of human epileptic brains (Proper et al., >>2000<<)." . _:b372877536 . _:b372877537 . _:b372877312 . _:b372877462 "4"^^ . _:b372877538 . _:b372877539 . _:b372877540 . _:b372877541 . _:b372877315 . _:b372877457 "4"^^ . . _:b372877542 . _:b372877543 . . _:b372877544 . _:b372877439 . _:b372877545 . . _:b372877314 . . _:b372877456 "4"^^ . _:b372877546 . _:b372877547 . _:b372877548 . _:b372877549 . _:b372877325 . . _:b372877459 "4"^^ . _:b372877550 . _:b372877551 . _:b372877520 . _:b372877521 . _:b372877324 . _:b372877458 "4"^^ . _:b372877522 . _:b372877523 . _:b372877524 . _:b372877418 . _:b372877525 . _:b372877327 . _:b372877469 "4"^^ . _:b372877526 . _:b372877527 . _:b372877777 . . . _:b372877528 . . _:b372877529 . _:b372877326 . _:b372877468 "4"^^ . _:b372877530 . _:b372877531 . . _:b372877532 . _:b372877533 . _:b372877321 . _:b372877471 "4"^^ . . _:b372877534 . _:b372877535 . _:b372877504 . _:b372877494 . _:b372877505 . _:b372877320 . _:b372877470 "4"^^ . _:b372877506 . _:b372877507 . _:b3291370 "The sections were subjected to silver enhancement and processed for electron microscopy as previously described (Boeckers et al., >>1999<<). The specimens were examined under an electron microscope (912; Carl Zeiss, Inc.) equipped with a spectroscopic filter (Omega Optical) and a charge-coupled device camera (2K; Gatan) operating at 80 kV." . _:b372877508 . . . _:b372877592 . _:b372877509 . _:b372877323 . _:b372877465 "4"^^ . _:b372877510 . _:b372877511 . _:b372877512 . _:b3291389 "of excitotoxic activity of kainate, we studied the effect of S24994 in cultures grown in the presence of picrotoxin (a GABAA receptor antagonist), a compound known to induce sprouting without causing cell damage (Koyama et al., >>2004<<). Examined after 10 DIV, the cultures treated with picrotoxin had very strong punctate synaptoporin IR throughout the DG granule cell and molecular layers (Fig." . _:b372877513 . _:b372878000 . _:b372877322 . . _:b372877464 "4"^^ . _:b372877514 . _:b372877515 . _:b372877516 . _:b372877517 . _:b372877333 . _:b372877467 "4"^^ . _:b372877518 . _:b372877519 . _:b372877488 . _:b372877489 . _:b372877332 . _:b372877466 "4"^^ . _:b372877490 . _:b372877491 . _:b372877492 . _:b372877636 . _:b372877493 . _:b372877335 . . _:b372877477 "4"^^ . _:b372877494 . _:b372877495 . . _:b372877496 . _:b372877497 . _:b372877543 . _:b372877334 . _:b372877476 "4"^^ . _:b372877498 . _:b372877499 . _:b372877671 . . . _:b372877500 . _:b372877501 . _:b372877329 . _:b372877479 "4"^^ . _:b372877502 . _:b372877503 . _:b372877472 . _:b372877473 . _:b372877328 . _:b372877478 "4"^^ . _:b372877474 . _:b372877475 . _:b372877476 . _:b372877657 . _:b372877477 . _:b372877331 . _:b372877473 "4"^^ . _:b372877478 . _:b372877479 . _:b372877480 . _:b372877481 . _:b372877330 . _:b372877472 "4"^^ . _:b372877482 . _:b372877483 . _:b372877484 . _:b372877485 . _:b372877927 . _:b372877341 . _:b372877475 "4"^^ . . _:b372877486 . _:b372877487 . _:b372877456 . _:b372877457 . . _:b372877340 . _:b372877474 "4"^^ . _:b372877458 . _:b372877459 . _:b372877460 . _:b372877461 . _:b372877485 "3"^^ . _:b372877343 . . _:b372877462 . _:b372877463 . _:b3291342 . _:b372877464 . _:b372878014 . _:b372877767 . _:b372877465 . . _:b372877484 "3"^^ . _:b372877342 . _:b372877466 . _:b372877467 . _:b372877884 . . _:b372877468 . _:b372877469 . _:b372877487 "3"^^ . _:b372877337 . _:b372877470 . _:b372877471 . _:b372877440 . . _:b372877441 . _:b372877486 "3"^^ . _:b372877336 . _:b372877442 . _:b372877443 . _:b372877297 . . _:b372877444 . _:b372877445 . _:b372877481 "3"^^ . _:b372877339 . _:b372877446 . _:b372877447 . _:b372877448 . _:b372877449 . _:b372877480 "3"^^ . _:b372877338 . _:b372877450 . _:b372877451 . _:b372877452 . _:b372877453 . _:b372877483 "3"^^ . _:b372877349 . _:b372877870 . _:b372877454 . _:b372877455 . _:b372877680 . _:b372877999 . _:b372877681 . _:b372877482 "3"^^ . _:b372877348 . _:b372877682 . _:b372877683 . . _:b372877684 . _:b372877685 . _:b372877493 "3"^^ . _:b372877351 . . _:b372877686 . _:b372877687 . _:b372877688 . _:b372877689 . _:b372877492 "3"^^ . _:b372877350 . _:b372877686 . _:b372877690 . _:b372877691 . . _:b372877692 . _:b372877693 . _:b372878015 . _:b372877495 "3"^^ . _:b372877345 . _:b372877694 . _:b372877695 . _:b372877664 . _:b372877665 . _:b372877494 "3"^^ . _:b372877701 . _:b3291340 . _:b372877666 . _:b372877344 . _:b372877667 . _:b372877597 . _:b372877412 . _:b372877668 . _:b372877669 . _:b372877489 "3"^^ . _:b372877347 . _:b372877670 . _:b372877671 . _:b372877672 . _:b372877673 . _:b372877488 "3"^^ . _:b372877684 . _:b372877346 . _:b372877674 . _:b372877662 . _:b372877675 . _:b372877676 . _:b372877677 . _:b372877828 . _:b372877627 . _:b372877491 "3"^^ . _:b372877357 . . _:b372877678 . _:b372877679 . _:b372877648 . _:b372877649 . _:b372877490 "3"^^ . _:b372877356 . _:b372877650 . _:b372877651 . _:b372877652 . _:b372877653 . _:b372877576 . _:b372877501 "3"^^ . _:b372877359 . _:b372877654 . _:b372877655 . _:b372877656 . _:b372877657 . _:b372877500 "3"^^ . _:b372877358 . _:b372877658 . _:b372877659 . _:b372877660 . _:b372877661 . _:b3291345 "Kainate is a neurotoxic agonist of glutamate receptors that induces severe status epilepticus, leading to neurodegeneration in all hippocampal subfields except for the dentate gyrus (DG; Sperk, >>1994<<). Instead of dying, the granule neurons of the DG undergo a sequence of plastic phenomena, including pruning of dendritic spines (Suzuki et al., 1997) and axonal sprouting that involves ingrowth of mossy fibers (granule cell axons) into" . _:b372877503 "3"^^ . _:b372877353 . _:b372877662 . _:b372877663 . _:b372877632 . _:b372877633 . _:b372877502 "3"^^ . _:b372877352 . _:b372877634 . _:b372877324 . . _:b372877635 . _:b372877636 . _:b372877591 . _:b372877637 . _:b372877497 "3"^^ . _:b372877355 . _:b372877638 . _:b372877639 . _:b372877640 . _:b372877605 . _:b372877641 . _:b372877496 "3"^^ . _:b372877354 . _:b372877642 . _:b372877643 . _:b372877858 . _:b372877644 . _:b3291380 "Thus, we confirmed our previous results, obtained by immunohistochemistry and Western blotting, showing an increase in MMP-9 IR in the DG after kainate administration (maximum at 72 h; Szklarczyk et al., >>2002<<)." . _:b372877645 . _:b372877810 . _:b372877499 "3"^^ . _:b372877365 . _:b3291350 "of the brain that initially does not induce seizures but eventually leads to lowering of the seizure threshold and, finally, to the occurrence of spontaneous seizures that are the hallmark of epilepsy (for review see Morimoto et al., >>2004<<). Kindling is not associated with overt neurodegeneration, yet it induces excessive sprouting of mossy fibers and synaptogenesis, mainly within the mossy fibers' normal terminal field, i.e., at the CA3 pyramidal cells' dendrites (Chen and" . _:b372877646 . _:b372877647 . _:b3291375 "We first used established techniques of in situ zymography in which a quenched fluorescent substrate (DQ gelatin) is applied to fresh-frozen tissue sections (Oh et al., 1999; Jourquin et al., >>2003<<). This approach, however, was totally unsatisfactory because tissue integrity was very poorly preserved, which was evident at the high magnifications required to visualize individual dendrites." . _:b372877616 . _:b3291374 . _:b372877617 . _:b372877498 "3"^^ . _:b372877364 . _:b372877618 . _:b372877619 . _:b372877620 . _:b372877621 . _:b372877509 "3"^^ . _:b372877367 . _:b372877622 . _:b372877623 . _:b372877624 . _:b372877625 . _:b372877508 "3"^^ . . _:b372877674 . _:b372877626 . _:b372877366 . _:b372877627 . _:b372877628 . _:b372877629 . _:b372877511 "3"^^ . _:b372877361 . _:b372877630 . _:b372877631 . _:b372877600 . _:b372877601 . _:b372877510 "3"^^ . _:b372877360 . _:b372877602 . _:b372877603 . _:b372877604 . _:b372877605 . _:b372877505 "3"^^ . _:b372877363 . _:b372877606 . _:b372877607 . _:b372877608 . _:b372877609 . _:b372877504 "3"^^ . _:b372877362 . _:b372877610 . _:b372877611 . _:b372877612 . _:b372877613 . _:b372877507 "3"^^ . _:b372877373 . _:b372877614 . _:b372877615 . _:b372877584 . . . _:b372877585 . _:b372877962 . _:b372877506 "3"^^ . _:b372877372 . _:b372877586 . _:b372877587 . _:b372877588 . _:b372877588 . _:b372877676 . _:b372877517 "3"^^ . _:b372877589 . _:b372877375 . _:b372877590 . _:b372877591 . _:b3291399 "Interestingly, recent in vivo imaging studies indicate that small spines are less stable, as they expand and collapse at much higher rates than the large ones (Matsuzaki et al., >>2004<<). If the MMP is involved in releasing dendritic spines from constraints imposed by neighboring structures and pericellular matrix, it would be expected that small and more dynamic spines have more of it. Furthermore, small and large spine" . _:b372877592 . _:b372877593 . _:b372877680 . _:b372877516 "3"^^ . _:b372877374 . _:b372877594 . _:b372877595 . _:b3291418 "Finally, similar to serine proteinases (Fernandez-Monreal et al., 2004; Kvajo et al., 2004), a proteolytic action of MMP-9 could be directly involved in some aspects of signal transmission (Michaluk and Kaczmarek, >>2007<<)." . _:b372877596 . _:b372877597 . _:b372877519 "3"^^ . _:b372877369 . _:b372877598 . _:b372877599 . _:b3291400 . . _:b372877568 . _:b372877569 . _:b372877518 "3"^^ . _:b372877368 . _:b3291342 "Recent studies also suggest that MMP-9 plays an important role in synaptic plasticity, learning, and memory (Szklarczyk et al., 2002; Meighan et al., 2006; Nagy et al., 2006; Okulski et al., 2007; Tian et al., >>2007<<). As epileptogenic plasticity involves extensive nervous tissue remodeling (Ben-Ari, 2001), we decided to examine the potential pathogenic role of MMP-9 in two distinct animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole" . _:b372877570 . _:b372877571 . _:b372877572 . . _:b372877573 . _:b372877513 "3"^^ . _:b372877371 . _:b372877574 . _:b372877575 . _:b372877576 . _:b372877577 . _:b372877512 "3"^^ . _:b372877370 . _:b372877578 . _:b372877579 . _:b372877580 . _:b372877581 . _:b372877515 "3"^^ . _:b372877381 . . _:b372877582 . _:b372877583 . _:b372877808 . _:b372877809 . _:b372877538 . _:b372877514 "3"^^ . _:b372877380 . _:b3291371 . _:b372877810 . _:b372877811 . _:b372877812 . _:b3291393 . _:b372877813 . _:b372877912 . _:b372877525 "3"^^ . _:b372877383 . _:b372877814 . _:b372877815 . _:b372877816 . _:b372877817 . _:b372877524 "3"^^ . _:b372877461 . _:b372877382 . _:b372878011 . _:b372877818 . _:b372877819 . _:b372877820 . _:b372877821 . _:b372877527 "3"^^ . _:b372877536 . _:b372877943 . _:b372877822 . _:b372877377 . _:b372877823 . _:b372877792 . _:b372877793 . _:b372877526 "3"^^ . _:b372877376 . _:b372877794 . _:b372877795 . . . _:b372877796 . _:b372877797 . _:b372877521 "3"^^ . _:b372877379 . _:b372877798 . _:b372877799 . _:b372877800 . _:b372877801 . _:b372877520 "3"^^ . _:b372877378 . _:b3291398 "observations that force us to revise the current concepts regarding the roles of MMP-9 in synaptic plasticity, concepts which are derived mainly from functional studies and light microscopic data (Nagy et al., 2006; Bozdagi et al., >>2007<<)." . _:b372877827 . _:b372877802 . _:b372877803 . _:b372877804 . _:b372877805 . _:b372877523 "3"^^ . _:b372877362 . _:b372877389 . _:b372877806 . _:b372877807 . _:b372877776 . _:b372877777 . _:b372877522 "3"^^ . _:b372877388 . _:b372877778 . _:b372877646 . _:b372877779 . _:b372877780 . _:b372877781 . _:b372877533 "3"^^ . _:b372877391 . . _:b372877782 . _:b372877783 . _:b372877784 . _:b372877785 . _:b372877532 "3"^^ . . _:b372877786 . _:b372877390 . _:b372877787 . . _:b372877788 . _:b372877789 . _:b372877856 . _:b372877535 "3"^^ . _:b372877385 . _:b372877790 . _:b372877791 . _:b372877760 . _:b372877761 . _:b372877534 "3"^^ . _:b372877384 . _:b372878016 . _:b372877762 . _:b372877763 . _:b372877878 . _:b372877764 . _:b372877765 . _:b372877529 "3"^^ . _:b372877387 . _:b372877766 . _:b372877767 . . _:b372877682 . _:b372877768 . _:b372877769 . _:b372877528 "3"^^ . _:b372877386 . _:b372877513 . _:b372877770 . . _:b372877955 . _:b372877771 . _:b372877772 . _:b372877773 . _:b372877531 "3"^^ . _:b372877397 . _:b372877774 . _:b372877775 . _:b3291396 "The different experimental approaches provided consistent results and are in agreement with Reeves et al. (>>2003<<), who demonstrated a beneficial effect of a general MMP inhibitor on the histological and behavioral outcome in an animal model of trauma-induced aberrant synaptic plasticity." . _:b372877919 . . _:b372877744 . _:b372877745 . _:b372877530 "3"^^ . _:b372877396 . _:b372877746 . . _:b372877812 . _:b372877747 . _:b372877748 . _:b3291402 "with transformation from silent (NMDAR only\u2013containing) to fully excitable (NMDAR- and AMPA-containing) synapses is associated with the enlargement and/or reshaping of the dendritic spines (Toni et al., 2001; Matsuzaki et al., >>2004<<). Notably, if these changes are precluded by the use of substances disrupting the F-actin cytoskeleton, potentiation does not occur (Fukazawa et al., 2003)." . _:b372877749 . . _:b372877541 "3"^^ . _:b372877399 . _:b372877750 . _:b372877751 . _:b372877752 . _:b3291422 . _:b372877753 . _:b372877540 "3"^^ . _:b372877398 . _:b372878013 . _:b372877388 . _:b372877754 . . _:b372877755 . _:b372877756 . . _:b372877757 . _:b372877543 "3"^^ . _:b372877393 . _:b372877614 . _:b372877758 . _:b372877759 . _:b372877728 . _:b372877729 . _:b372877542 "3"^^ . _:b372877392 . _:b372877730 . . _:b372877731 . _:b372877732 . _:b372877733 . _:b372877537 "3"^^ . _:b372877395 . . . _:b372877734 . _:b372877735 . _:b372877736 . _:b3291401 . _:b372877737 . _:b372877536 "3"^^ . _:b372877394 . _:b372877738 . _:b372877739 . _:b372877740 . _:b372877741 . . _:b372877539 "3"^^ . _:b372877405 . . _:b372877742 . . _:b372877743 . _:b372877712 . . _:b372877538 "3"^^ . _:b372877713 . _:b372877404 . . _:b372877714 . _:b372877715 . _:b372877716 . . _:b372877717 . _:b372877549 "3"^^ . _:b372877407 . _:b372877356 . _:b372877718 . _:b372877719 . _:b372877720 . . _:b372877721 . _:b372877548 "3"^^ . _:b372877406 . _:b372877722 . _:b372877723 . _:b372877639 . _:b372877487 . _:b372877724 . _:b372877725 . _:b372877551 "3"^^ . _:b372877401 . _:b372877726 . _:b372877727 . _:b372877696 . _:b372877697 . _:b372877550 "3"^^ . _:b372877400 . _:b372877951 . . _:b372877698 . . _:b372877699 . _:b372877700 . _:b372877701 . _:b372877545 "3"^^ . _:b372877403 . _:b372877702 . _:b372877363 . _:b372877703 . _:b372877704 . _:b372877705 . . _:b372877544 "3"^^ . _:b372877402 . _:b3291392 "We pursued this intriguing finding by demonstrating that TIMP1 was in fact a neuronal target of the activity-dependent transcription factor AP1 (Jaworski et al., >>1999<<) and was up-regulated by seizures throughout the entire hippocampus." . _:b372877706 . _:b372877707 . _:b372877708 . . _:b372877709 . _:b372877547 "3"^^ . _:b372877413 . _:b372877710 . _:b372877711 . _:b372877936 . _:b372877953 . _:b372877937 . _:b3291414 . _:b372877546 "3"^^ . _:b372877412 . _:b372877938 . _:b372877939 . _:b372877940 . _:b372877941 . _:b372877557 "3"^^ . _:b372877415 . _:b372877942 . _:b372877943 . _:b372877944 . _:b372877945 . _:b372877556 "3"^^ . _:b372877414 . _:b372877971 . _:b372877946 . _:b372877947 . _:b372877948 . _:b372877949 . _:b372877559 "3"^^ . _:b372877409 . _:b372877825 . _:b372877950 . _:b372877951 . _:b372877993 . _:b372877607 . _:b372877920 . _:b372877921 . _:b372877558 "3"^^ . . _:b372877408 . _:b372877922 . _:b372877923 . _:b372877924 . _:b372877925 . _:b372877553 "3"^^ . _:b372877411 . _:b372877926 . _:b372877927 . . _:b372877928 . _:b372877929 . _:b372877552 "3"^^ . _:b372877410 . _:b372877930 . _:b372877931 . _:b372877932 . _:b372877933 . _:b372877555 "3"^^ . _:b372877421 . _:b372877934 . _:b372877935 . _:b372877907 . _:b372877904 . _:b372877905 . _:b372877554 "3"^^ . _:b372877420 . _:b372877906 . _:b372877907 . _:b372877908 . _:b372877909 . _:b372877565 "3"^^ . _:b372877423 . . _:b372877910 . _:b372877911 . . _:b372877912 . _:b372877913 . _:b372877564 "3"^^ . . _:b372877914 . _:b372877422 . _:b372877915 . _:b372877916 . _:b372877596 . _:b372877917 . _:b372877727 . _:b372877567 "3"^^ . . _:b372877918 . _:b372877417 . _:b372877919 . _:b372877414 . _:b372877888 . . _:b372877566 "3"^^ . _:b372877889 . _:b372877416 . _:b372877890 . _:b372877891 . _:b372877442 . _:b372877892 . _:b372877893 . _:b372877784 . _:b372877561 "3"^^ . _:b372877435 . _:b372877419 . _:b372877563 . _:b372877894 . _:b372877530 . _:b372877895 . . _:b372877896 . _:b372877897 . _:b372877560 "3"^^ . _:b372877418 . _:b372877898 . _:b372877899 . _:b372877900 . _:b372877901 . _:b372877563 "3"^^ . _:b372877429 . _:b372877902 . _:b372877903 . _:b372877872 . _:b3291427 "Among MMPs, only MMP-7 and MMP-24 have been added to this group so far (Bilousova et al., 2006; Monea et al., >>2006<<; for review see Ethell and Ethell, 2007)." . _:b372877873 . _:b372877562 "3"^^ . _:b372877428 . _:b372877874 . _:b372877875 . _:b372877351 . _:b372877876 . _:b372877877 . _:b372877573 "3"^^ .