Local interactions between hippocampal neurons

描述（申请人提供）：许多研究分析了颞叶癫痫动物模型的轴突萌发和局部兴奋回路的突触重组，但在单神经元水平上对癫痫发生过程中局部抑制回路重组的电生理研究相对较少。此外，在重复突触激活期间，这些重组电路的动态特性，正如在海马癫痫发作期间所预期的那样，是相对未知的。在拟议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变化是什么，以及这些回路重复激活期间的突触抑制是否有助于慢性癫痫发生期间的癫痫传播？该实验将使用海碱盐诱导癫痫大鼠的海马切片，以确定癫痫持续状态后突触输入的丧失和随后的突触重组如何导致齿状回局部抑制回路和CA1区抑制回路在SE后的变化。该实验将解决以下具体问题：(1)海马主要神经元的轴突芽化(例如，齿状颗粒细胞和CA1锥体细胞)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枝，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如何改变通过该网络的传输，以及这些海马区域是否在癫痫持续状态后发生复发性自发癫痫发作时对重复激活异常敏感？目的3将利用重复刺激的频率来模拟在盐酸盐诱导的癫痫大鼠长期记录的电痉挛发作时观察到的突触激活模式。这些实验旨在增加对可能导致颞叶癫痫的抑制回路重组的理解。以及局部抑制回路的活动依赖性抑制如何促进癫痫发作的扩散。这些系统是治疗干预的主要目标，以预防难治性颞叶癫痫患者的癫痫发作。

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.