MOSSY FIBER GRANULE CELL SYNAPSES

海马齿状回内复发性苔藓纤维生长是颞叶癫痫的独特特征。新的苔藓纤维颗粒细胞连接的形成极大地扩展了通常非常有限的单突触经常性兴奋回路。有人提出，该回路通过降低齿状回对癫痫传播的阻力而参与癫痫的发生。该项目的目标是发现这些突触最有可能促进癫痫发作传播的条件，并确定可以作为治疗靶点的突触特性。目前对苔藓纤维颗粒细胞突触的生理学和药理学知之甚少；拟议的项目旨在填补这一空白。匹罗卡品治疗的大鼠成为癫痫患者，并发展出持续致密的复发性苔藓纤维通路，将用于研究突触功能的三个方面。首先，将确定苔藓纤维-CA3锥体细胞突触的三种形式的突触前可塑性的特征和激发苔藓纤维路径所需的条件。这些研究将确定颗粒细胞活动的模式，这些模式最有可能驱动强烈的单突触反馈兴奋。由于初步结果表明匹罗卡品诱导的癫痫持续状态增强了NMDA受体对突触反应的贡献，另一项研究将确定癫痫脑中苔藓状纤维颗粒细胞突触是否表现出一种NMDA依赖的长时程增强形式。其次，将分析海人酸受体和代谢型谷氨酸受体对突触反应的影响。这项研究的一个目标是评估这些受体作为针对复发苔藓纤维通路的药物的潜在治疗靶点。最后，通过苔藓纤维刺激释放的锌改变颗粒细胞的GABA/A、NMDA、AMPA和海人藻酸受体功能的能力将通过使用不受高聚焦紫外光作用的激动剂来评估。这项研究将确定复发的苔藓纤维是否也可能通过修改突触后谷氨酸受体来影响癫痫发作。

Recurrent mossy fiber growth in the hippocampal dentate gyrus is a unique feature of temporal lobe epilepsy. The formation of new mossy fiber-granule cell connections greatly expands a monosynaptic recurrent excitatory circuit that is normally very limited. It has been proposed that the circuit contributes to epileptogenesis by diminishing the resistance of the dentate gyrus to seizure propagation. The objective of this project is to discover the conditions under which these synapses are most likely to facilitate seizure propagation and to identify synaptic properties that could serve as therapeutic targets. Little is currently known about the physiology and pharmacology of mossy fiber- granule cell synapses; the proposed project is intended to fill this gap. Pilocarpine-treated rats, which become epileptic and also develop a consistently dense recurrent mossy fiber pathway, will be used to investigate three aspects of synaptic function. First, the characteristics of and the conditions needed to provoke three forms of presynaptic plasticity identified at mossy fiber-CA3 pyramidal cell synapses will be determined for the recurrent mossy fiber pathway. These studies will define the patterns of granule cell activity that are most likely to drive strong monosynaptic feedback excitation. Because preliminary results suggest that pilocarpine-induced status epilepticus enhances the contribution of NMDA receptors to the synaptic response, another study will determine whether mossy fiber-granule cell synapse on the epileptic brain exhibit an NMDA-dependent form of long term potentiation. Second, the involvement of kainate and metabotropic glutamate receptors to the synaptic response will be analyzed. One goal of this study is to evaluate these receptors as potential therapeutic targets of drugs directed against the recurrent mossy fiber pathway. Finally, the ability of zinc released by mossy fiber stimulation to alter GABA/A, NMDA, AMPA and kainate receptor function in granule cells will be assessed with use of agonists uncaged by highly focused ultraviolet light. This study will determine whether recurrent mossy fibers might also influence seizures through modification of postsynaptic glutamate receptors.