MODULATION OF SYNAPTIC EFFICACY & MECHANISMS OF EPILEPSY

这项研究的目的是通过以下方式了解其生理机制 海马区的兴奋和抑制可以通过以下哪种方式来调节 基于激活模式的相对较短的时间段 Synapse。我们的假设是，信号的差动调制 兴奋性和抑制性突触的功效是有原因的，至少在 部分，用于相对稳定的发作间期活动和 缉获和从重点区域扩散缉获活动 中枢神经系统正常区域的异常。通过增加我们对 这些过程，希望有新的预防或治疗策略 会发展成癫痫。 这些实验将在一种新的非常低的制剂中进行 大鼠海马神经元密度分离培养。录制将是 用来自单个神经元的全细胞膜片钳电极和 孤立的两个突触相连的神经元。突触 神经元之间的相互作用也将通过组织学进行分析 技巧。微型突触电位的性质，既包括微型突触电位，也包括微型突触电位。 将检查EPSC和迷你IPSC，并将确定它们是否 表现出量子假说所预言的那样。迷你PSC的变化 将使用幅度、形状或频率来帮助确定频率 突触效能的依赖性改变是由于突触前或 突触后因素。一旦确定了这一点，涉及的机制 将会被确定。 以下假设将被直接检验：(1)兴奋性和 海马神经元之间的抑制性突触在以下情况下表现不同 在中频或高频时激活。(2)神经递质释放 兴奋性和抑制性的特征有很大的不同 类似生理条件下的突触。(3)突触 培养的海马神经元之间的传递可以用 量子假说。(4)抑制中的频率依赖递减 突触的作用主要是由于突触前机制。(5) 兴奋性突触效能的频率依赖性增加是应该的 部分与突触前机制有关。(6)突触后受体的变化 属性可能对频率依赖效应起到作用，这是 更突出地参与兴奋性突触功能的增加。 在这些实验结束时，作为频率基础的机制- 兴奋性突触的依赖增强和抑制的减少 突触将会被更好地理解。这样就有可能 将这些发现外推到适当的癫痫模型(切片 准备工作或动物模型)，以检验这些变化在 突触的效能在全部或部分上对这种转变负责。 致痫区域内的癫痫发作和癫痫发作活动的扩散 从癫痫灶到皮质的正常区域。使用选择性的方法 为了防止或扭转这些影响，希望最终， 癫痫发作是可以预防或抑制的。

The goal of this research is to understand the physiological mechanisms by which excitation and inhibition in the hippocampus can be modulated over relatively short time periods based on patterns of activation of the synapse. It is our hypothesis that the differential modulation of excitatory and inhibitory synaptic efficacy is responsible, at least in part, for the transition between relatively stable interictal activity and seizures and for the spread of seizure activity from areas of focal abnormality to normal areas of CNS. By increasing our understanding of these processes, it is hoped that new strategies for preventing or treating epilepsy will be developed. These experiments will be carried out in a new preparation of very low density dissociated cultures of rat hippocampal neurons. Recording will be made with whole cell patch clamp electrodes from single neurons and from isolated pairs of synaptically connected neurons. The synaptic interactions between the neurons will also be analyzed with histological techniques. The properties of miniature synaptic potentials, both mini- EPSCs and mini-IPSCs, will be examined and it will be determined if they behave as predicted by the quantum hypothesis. Changes in mini-psc amplitude, shape or frequency will be used to help determine if frequency dependent changes in synaptic efficacy are due to presynaptic or postsynaptic factors. Once this is determined, the mechanisms involved will be ascertained. The following hypotheses will be directly tested: (1) Excitatory and inhibitory synapses between hippocampal neurons behave differently when activated at moderate or high frequencies. (2) Neurotransmitter release characteristics are substantially different for excitatory and inhibitory synapses under comparable physiological conditions. (3) Synaptic transmission between hippocampal neurons in culture can be described by the quantum hypothesis. (4) Frequency dependent decrement in inhibitory synaptic efficacy is due predominantly to presynaptic mechanisms. (5) Frequency dependent increment in excitatory synaptic efficacy is due partially to presynaptic mechanisms. (6) Changes in postsynaptic receptor properties may contribute to the frequency dependent effects and this is more prominently involved in the increment of excitatory synaptic function. At the end of these experiments, the mechanisms which underlie frequency- dependent potentiation of excitatory synapses and decrement of inhibitory synapses will be better understood. It will then be possible to extrapolate these findings to an appropriate epilepsy model (a slice preparation or animal model) to test the hypothesis that these changes in synaptic efficacy are responsible in whole, or in part, for the transition to seizures in an epileptogenic area and for the spread of seizure activity from a seizure focus to normal areas of cortex. Using selective methods for preventing or reversing these effects, it is hoped that, ultimately, seizures can be prevented or suppressed.