MODULATION OF SYNAPTIC EFFICACY & MECHANISMS OF EPILEPSY

有人提出，癫痫样活动的发展， 发作间期尖峰和癫痫发作之间的过渡，以及 癫痫发作从异常到正常的大脑都是，至少部分，由于 兴奋性和抑制性突触功能的差异 对中度和高频率激活作出反应。 该基金建议 首先测试假设，在相同的生理条件下， 条件下，皮层抑制性突触的功效降低， 皮层兴奋性突触增强。 如果发现是真的， 然后将提出假设来解释这些机制， 是突触功效变化的基础， 使用哺乳动物新皮层和海马的分离细胞培养物 as model模型systems系统. 细胞内记录从前和 突触后神经元的对，这是耦合的兴奋性和 抑制连接将与两个常规的 微电极和WC贴片微电极。 突触前和/或 参与抑制性突触减量的突触后因子将被 测定 突触后机制，如受体的变化 重复激活（脱敏）期间的敏感性， 引起IPSP明显变化的C1平衡电位 功效，或通过抑制剂激活其他通道 高浓度或长时间暴露期间的神经递质 将对受体进行研究。 突触前机制，如 抑制性中间神经元高频率放电的能力 重复激活，神经递质释放的特点 在兴奋性和抑制性突触，和GABA的能力， 激活突触前GABAA或GABAB受体， 还将检查突触前抑制剂。 兴奋性和抑制性突触将被分析的技术 的量子分析和兴奋性的释放特性， 和抑制性神经递质进行比较， 通过泊松或二项统计充分描述释放， 二价阳离子浓度的变化如何影响 神经传递素 量子分析也将用于进一步 定义频率的前或后突触机制 抑制性突触功效的依赖性变化。 人们希望，增加对生理学的理解， 哺乳动物兴奋性和抑制性突触功能的调节 皮质将有助于发展改进的战略， 治疗癫痫，特别是用于预防 相对良性的发作间期异常和更具破坏性的 癫痫。

It has been proposed that the development of epileptiform activity, the transition between interictal spikes and seizures, and the spread of seizures from abnormal to normal brain are all, at least partially, due to differences in the way excitatory and inhibitory synaptic function respond to moderate and high frequency activation. This grant proposes to first test the hypothesis that under identical physiological conditions, cortical inhibitory synapses decrease in efficacy while cortical excitatory synapses potentiate. If found to be true, new hypotheses will then be developed to explain the mechanisms which underlie such changes in synaptic efficacy and these will be tested using dissociated cell cultures of mammalian neocortex and hippocampus as model systems. Intracellular recording from both the pre and postsynaptic neurons of pairs which are coupled by excitatory and inhibitory connections will be performed with both conventional microelectrodes and WC patch microelectrodes. The presynaptic and/or postsynaptic factors involved in inhibitory synaptic decrement will be determined. Postsynaptic mechanisms such as changes in receptor sensitivity during repetitive activation (desensitization), a shift in the C1 equilibrium potential causing an apparent change in IPSP efficacy, or activation of other channels by the inhibitory neurotransmitter at higher concentrations or during prolonged exposures to the receptor will be investigated. Presynaptic mechanisms such as the ability of inhibitory interneurons to fire with high frequency repetitive activation, the characteristics of neurotransmitter release at excitatory and inhibitory synapses, and the ability of GABA to activate presynaptic GABAA or GABAB receptors which then act as presynaptic inhibitors will also be examined. Excitatory and inhibitory synapses will be analyzed with the techniques of the quantal analysis and the release characteristics of excitatory and inhibitory neurotransmitters will be compared to determine whether release is adequately described by Poisson or binomial statistics, and how changes in divalent cation concentrations influence release of neurotransmitter. The quantal analysis will also be used to further define the pre or postsynaptic mechanisms which underlie frequency dependent changes in inhibitory synaptic efficacy. It is hoped that an increased understanding of the physiological regulation of excitatory and inhibitory synaptic function in mammalian cortex will contribute toward the development of improved strategies for treating epilepsy, and especially for preventing the transition between relatively benign interictal abnormalities and the much more disruptive seizure.