Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus
Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus
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DOI：
10.1523/jneurosci.2045-04.2004
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发表时间：
2004-08-18
影响因子：
5.3
通讯作者：
Ikegaya, Y
中科院分区：
文献类型：
--
作者：
Koyama, R;Yamada, MK;Ikegaya, Y
苔藓纤维（MF）轴突的异常萌芽和突触重组常见于颞叶癫痫患者的海马体中，并导致齿状回中兴奋性反馈环的形成，这是癫痫反复发作的假定细胞基础。使用离体海马培养物，我们表明，长时间的过度活跃会诱导 MF 萌芽和由此产生的网络重组，并且脑源性神经营养因子 (BDNF) 对于引发这些致病可塑性是必要且充分的。过度兴奋诱导 MF 通路中 BDNF 蛋白表达上调，这是由 L 型 Ca2+ 通道介导的效应。神经营养蛋白受体酪氨酸激酶 (Trk)B 抑制剂 K252a 或功能阻断性抗 BDNF 抗体可防止多动诱导的 MF 萌芽。即使在神经活动阻断的情况下，将 BDNF 局部应用于门部（而非其他分区）也能够启动 MF 轴突重塑，最终导致齿状超兴奋。用显性失活 TrkB 转染颗粒细胞可防止轴突分支。因此，L型Ca2+通道的过度激活导致颗粒细胞表达BDNF，并且细胞外释放的BDNF刺激存在于MF的肺门段上的TrkB受体以诱导轴突分支，这可能建立超兴奋的齿状回路。
Aberrant sprouting and synaptic reorganization of the mossy fiber (MF) axons are commonly found in the hippocampus of temporal lobe epilepsy patients and result in the formation of excitatory feedback loops in the dentate gyrus, a putative cellular basis for recurrent epileptic seizures. Using ex vivo hippocampal cultures, we show that prolonged hyperactivity induces MF sprouting and the resultant network reorganizations and that brain-derived neurotrophic factor (BDNF) is necessary and sufficient to evoke these pathogenic plasticities. Hyperexcitation induced an upregulation of BDNF protein expression in the MF pathway, an effect mediated by L-type Ca2+ channels. The neurotrophin receptor tyrosine kinase (Trk)B inhibitor K252a or function-blocking anti-BDNF antibody prevented hyperactivity-induced MF sprouting. Even under blockade of neural activity, local application of BDNF to the hilus, but not other subregions, was capable of initiating MF axonal remodeling, eventually leading to dentate hyperexcitability. Transfecting granule cells with dominant-negative TrkB prevented axonal branching. Thus, excessive activation of L-type Ca2+ channels causes granule cells to express BDNF, and extracellularly released BDNF stimulates TrkB receptors present on the hilar segment of the MFs to induce axonal branching, which may establish hyperexcitable dentate circuits.