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之间的过渡，以及 从异常大脑到正常大脑的癫痫发作都是，至少部分是由于 兴奋性和抑制性突触功能方式的差异 对中高频率的激活做出反应。这项拨款建议 首先测试假设，在相同的生理条件下 条件下，皮层抑制性突触的有效性降低，而 皮质兴奋性突触增强。如果被发现是真的，新的 然后将开发假说来解释 突触效力的这些变化是基础，这些将得到测试 用分离的哺乳动物大脑皮层和海马区细胞培养 作为模型系统。Pre和Pre的细胞内记录 兴奋性和突触后神经元对的突触后神经元 抑制性连接将与两种常规连接一起执行 微电极和WC贴片微电极。突触前和/或 参与抑制性突触减少的突触后因素将是 下定决心。突触后机制，如受体的变化 在重复激活(脱敏)过程中的敏感性， 引起IPSP明显变化的C1平衡电势 有效，或通过抑制激活其他通道 较高浓度或长时间暴露时的神经递质 对受体的影响将被研究。突触前机制，如 抑制性中间神经元高频放电的能力 神经递质释放的特征--重复激活 兴奋性和抑制性突触，以及GABA 激活突触前GABAA或GABAB受体，然后作为 突触前抑制物也将被检查。 兴奋性和抑制性突触将用这项技术进行分析 的量子分析和兴奋性物质的释放特性 和抑制性神经递质进行比较，以确定 用泊松或二项式统计量可以很好地描述释放 二价阳离子浓度的变化对药物释放的影响 神经递质。量化分析还将用于进一步 定义构成频率基础的突触前或突触后机制 抑制性突触效能的依赖性变化。 希望通过增加对生理学知识的了解 哺乳动物兴奋性和抑制性突触功能的调节 皮质将有助于制定改进的战略， 治疗癫痫，特别是防止癫痫之间的过渡 相对良性的发作间期异常和更具破坏性的 癫痫发作。

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.