Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus
Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus
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DOI：
10.1523/jneurosci.3118-11.2011
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发表时间：
2011-09-07
影响因子：
5.3
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
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作者：
Mizoguchi, Hiroyuki;Nakade, Junya;Yamada, Kiyofumi
反复发作的癫痫活动已被证明会引起大脑中各种永久性的结构变化。基质金属蛋白酶（MMPs）主要通过切割细胞外基质蛋白来促进神经元的可塑性。在这里，我们研究了MMP-9在戊四唑（PTZ）诱发的小鼠点燃性癫痫发作中的作用。反复给予PTZ （40 mg/kg）可引起点燃性癫痫发作，并伴有海马中MMP-9活性和表达增强。单次给药（60 mg/kg）后，全身性强直性癫痫小鼠海马组织中MMP-9活性未见变化。MMP-9在点燃小鼠海马齿状回中与神经元标记物NeuN和胶质标记物GFAP共定位。地西泮或MK-801与PTZ共给药可抑制点燃的发生和海马中MMP-9水平的升高。与野生型小鼠相比，在MMP-9（(-/-)）小鼠中观察到反复PTZ治疗对点燃性癫痫进展的显著抑制，这一观察结果伴随着海马成熟脑源性神经营养因子水平的降低。在每次PTZ治疗前向右心室微注射BDNF清扫剂TrkB-Fc可显著抑制野生型小鼠的点燃发生，而在MMP-9（(-/-)）小鼠中未观察到任何影响。另一方面，双侧向海马齿状回注射pro-BDNF可显著增强野生型小鼠的点燃，但对MMP-9（(-/-)）型小鼠没有作用。这些发现表明，MMP-9参与了点燃小鼠行为表型的进展，因为海马中前BDNF转化为成熟BDNF。
Recurrent seizure activity has been shown to induce a variety of permanent structural changes in the brain. Matrix metalloproteinases (MMPs) function to promote neuronal plasticity, primarily through cleavage of extracellular matrix proteins. Here, we investigated the role of MMP-9 in the development of pentylenetetrazole (PTZ)-induced kindled seizure in mice. Repeated treatment with PTZ (40 mg/kg) produced kindled seizure, which was accompanied by enhanced MMP-9 activity and expression in the hippocampus. No change in MMP-9 activity was observed in the hippocampi of mice with generalized tonic seizure following single administration of PTZ (60 mg/kg). MMP-9 colocalized with the neuronal marker NeuN and the glial marker GFAP in the dentate gyrus of the kindled mouse hippocampus. Coadministration of diazepam or MK-801 with PTZ inhibited the development of kindling and the increased MMP-9 levels in the hippocampus. Marked suppression of kindled seizure progression in response to repeated PTZ treatment was observed in MMP-9((-/-)) mice compared with wild-type mice, an observation that was accompanied by decreased hippocampal levels of mature brain-derived neurotrophic factor. Microinjecting the BDNF scavenger TrkB-Fc into the right ventricle before each PTZ treatment significantly suppressed the development of kindling in wild-type mice, whereas no effect was observed in MMP-9((-/-)) mice. On the other hand, bilateral injections of pro-BDNF into the hippocampal dentate gyrus significantly enhanced kindling in wild-type mice but not MMP-9((-/-)) mice. These findings suggest that MMP-9 is involved in the progression of behavioral phenotypes in kindled mice because of conversion of pro-BDNF to mature BDNF in the hippocampus.