MOSSY FIBER GRANULE CELL SYNAPSES

海马齿状回中反复生长的苔藓纤维是颞叶癫痫的一个独特特征。新的苔藓状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循环兴奋回路。有人提出，该回路通过减少齿状回对癫痫发作传播的抵抗力而有助于癫痫发生。该项目的目的是发现这些突触最有可能促进癫痫发作传播的条件，并确定可能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，也发展出一贯密集的复发苔藓纤维通路，将用于研究突触功能的三个方面。首先，在苔藓纤维- ca3锥体细胞突触中发现的三种形式的突触前可塑性的特征和引发所需的条件将被确定为苔藓纤维通路的复发。这些研究将确定最有可能驱动强单突触反馈兴奋的颗粒细胞活动模式。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大脑上的苔藓纤维颗粒细胞突触是否表现出依赖NMDA的长期增强形式。其次，将分析海因酸盐和代谢性谷氨酸受体对突触反应的参与。本研究的目的之一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，通过使用高聚焦紫外光释放的激动剂，评估苔藓纤维刺激释放的锌改变颗粒细胞中GABA/A、NMDA、AMPA和盐酸盐受体功能的能力。本研究将确定复发苔藓纤维是否也可能通过突触后谷氨酸受体的修饰影响癫痫发作。

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.