Local interactions between hippocampal neurons

描述（由申请人提供）：许多研究分析了颞叶癫痫动物模型中局部兴奋回路的轴突发芽和突触重组，但相对较少在单神经元水平上对癫痫发生过程中局部抑制回路的重组进行电生理研究。 此外，在海马癫痫发作期间预期的重复突触激活期间这些重组回路的动态特性相对未知。在所提出的实验中要解决的一般问题是癫痫持续状态后局部抑制回路的短期和长期改变是什么，在这些回路的重复激活过程中，突触抑制是否有助于慢性癫痫发生过程中的癫痫发作传播？所提出的实验将使用来自具有红藻氨酸诱导的癫痫的大鼠的海马切片来确定癫痫持续状态后突触输入的损失和随后的突触重组如何导致齿状回和CA 1区中的局部抑制回路的变化。SE后这两个海马区中的抑制回路似乎不同。实验将解决以下具体问题（1）海马主要神经元（如齿状颗粒细胞和CA 1区锥体细胞）的轴突出芽是否导致抑制性中间神经元上功能性兴奋性突触的形成？(2)中间神经元是否长出轴突侧支，并与主神经元形成新的抑制性突触？(3)局部抑制回路的重复激活是如何改变通过该网络的传输的？在癫痫持续状态后，当复发性自发性癫痫发作发生时，海马的这些区域是否对重复激活异常敏感？目的3将利用重复刺激的频率，模拟在患有红藻氨酸诱导的癫痫的大鼠中慢性记录的电图癫痫发作时观察到的突触激活模式。这些实验旨在提供对可能导致颞叶癫痫的抑制回路的重组的更多理解，以及活动-局部抑制回路的依赖性抑制可能促进癫痫发作的传播。待研究的系统是治疗干预的主要目标，以预防癫痫患者的癫痫发作。顽固性颞叶癫痫

DESCRIPTION (provided by applicant): Many studies have analyzed axonal sprouting and synaptic reorganization of local excitatory circuits in animal models of temporal lobe epilepsy, but relatively little electrophysiological research at the single-neuron level has been conducted on reorganization of local inhibitory circuits during epileptogenesis. Furthermore, the dynamic properties of these reorganized circuits during repetitive synaptic activation, as expected during the onset of hippocampal seizures, are relatively unknown The general questions to be addressed in the proposed experiments are what are the short- and long-term alterations in local inhibitory circuits after status epilepticus, and does synaptic depression during repetitive activation of these circuits contribute to seizure propagation during chronic epileptogenesis? The proposed experiments will use hippocampal slices from rats with kainate-induced epilepsy to determine how loss of synaptic input and subsequent synaptic reorganization after status epilepticus leads to changes in local inhibitory circuits in the dentate gyrus and the CA1 area Inhibitory circuits in these two hippocampal areas appear to be different after SE The experiments will address the following specific questions (1) Does axonal sprouting of principal neurons in the hippocampus (e g, dentate granule cells and CA1 pyramidal cells) lead to formation of functional excitatory synapses on inhibitory interneurons? (2) Do interneurons sprout axon collaterals, and form new inhibitory synapses with principal neurons? (3) How does repetitive activation of local inhibitory circuits alter transmission through this network, and are these areas of the hippocampus abnormally sensitive to repetitive activation at periods after status epilepticus when recurrent spontaneous seizures occur? Aim 3 will utilize frequencies of repetitive stimulation that simulate the patterns of synaptic activation observed at the onset of chronically recorded electrographic seizures in rats with kainate-induced epilepsy These experiments aim to provide increased understanding about the reorganization of inhibitory circuits that may contribute to temporal lobe epilepsy, and how activity-dependent depression of local inhibitory circuits may promote the spread of epileptic seizures The systems to be investigated are prime targets for therapeutic intervention to prevent seizures in people with intractable temporal lobe epilepsy.