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，但在单个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的电生理学研究相对较少。此外，在重复激活突触的过程中，这些重新组织的回路的动态特性是相对未知的。在拟议的实验中需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过程中癫痫的传播？本实验将使用海人酸致癫痫大鼠的海马片，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电路的变化，以及SE后这两个海马区CA1区抑制电路的变化。实验将解决以下具体问题：1)海马区主要神经元(如齿状颗粒细胞和CA1锥体细胞)的轴突萌芽是否导致对中间神经元的抑制性功能性兴奋性突触的形成？(2)中间神经元发出轴突侧支，并与主神经元形成新的抑制性突触？(3)局部抑制电路的重复激活如何改变通过该网络的传递，以及当癫痫持续状态发生时，海马区的这些区域对重复激活异常敏感吗？目的3将利用重复刺激的频率，模拟在海人酸致癫痫大鼠慢性记录癫痫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的重组的理解，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。将要研究的系统是治疗干预的主要靶点，以防止顽固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.