Impact of Early-Life Seizures on Synaptic Plasticity

对发育性癫痫的机制知之甚少，即，从生命早期的发作性癫痫发展到成年期的慢性癫痫。这种进展可能导致儿童学习障碍，可以通过更好地了解这一过程来预防。在学习、长期抑郁（LTD）和癫痫发生后果的体外相关性表达之间存在机械联系：LTD通过N-乙基马来酰亚胺敏感融合蛋白（NSF）诱导突触中特异性GluR亚基（GluR 2）几乎完全清除，依赖性机制，而癫痫样放电在体外可以产生LTD和癫痫发生导致受损的LTD。我假设这两个过程，LTD的表达和癫痫发生饱和了相同的NSF-GIuR 2相互作用，其减少了突触GIuR 2受体的数量并导致慢性LTD损伤。首先，LTD在对照组和癫痫大鼠海马脑片的发育进程将使用现场记录技术进行研究。将用海马下破伤风毒素注射方法诱导发育性癫痫发生。据推测，癫痫大鼠将开发一个渐进性的损害海马LTD. Second的表达，与NSF的发展相互作用的GluRs将研究使用全细胞膜片钳记录的GluR介导的突触电流沿着与药理学药物，调节G1 uR 2-NSF相互作用的切片制剂从癫痫和对照大鼠在不同年龄。假设癫痫发生将饱和，从而阻断GluR 2-NSF相互作用的进一步药理学破坏。最后，发展性癫痫引起的LTD的损害也可能是单通道和/或动力学性质的GluRs的改变的结果。假设癫痫大鼠中的GluR单通道电导和动力学（通过GluR介导的突触电流的全树突膜片钳记录和非稳态噪声分析测量）将与对照大鼠中测量的值相似。

Little is understood about the mechanisms developmental epilepsy, i.e., the progression from episodic seizures in early-life to chronic epilepsy in adulthood. This progression likely causes childhood learning impairment that could be prevented by a better understanding of the process. A mechanistic connection exists between the expression of an in vitro correlate of learning, long-term depression (LTD), and the consequences of epileptogenesis: LTD induces a near complete removal of a specific GluR subunit (GluR2) from synapses by an N-ethyl-maleimide-sensitive fusion protein (NSF) -dependent mechanism while epileptiform discharges in vitro can produce LTD and epileptogenesis leads to impaired LTD. I hypothesize that these two processes, the expression of LTD and epileptogenesis, saturate the same NSF-GIuR2 interaction that decreases the number of synaptic GIuR2 receptors and results in chronic LTD impairment. First, the developmental progression of LTD in hippocampal slices from control and epileptic rats will be studied using field-recording techniques. Developmental epileptogenesis will be induced with the infra-hippocampal tetanus toxin injection method. It is hypothesized that epileptic rats will develop a progressive impairment in the expression of hippocampal LTD. Second, the developmental interaction of GluRs with NSF will be studied using whole-cell patch-clamp recordings of GluR mediated synaptic currents along with pharmacological agents that modulate the G1uR2-NSF interaction in slice preparations from epileptic and control rats at different ages. It is hypothesized that epileptogenesis will saturate and thus occlude further pharmacological disruption of the GluR2-NSF interaction. Lastly, the impairment of LTD caused by developmental epileptogenesis could alternatively be the result of alterations in the single-channel and/or kinetic properties of GluRs. It is hypothesized that G1uR single- channel conductance and kinetics in epileptic rats, measured by whole- dendrite patch-clamp recordings of GluR mediated synaptic currents and non-stationary noise analysis, will be similar to values measured in control rats.