Modulation of Neocortical Interneuronal Function

项目总结： 突触前控制兴奋性和抑制性突触传递的机制 大脑皮层在正常信息处理中起着关键作用，也可能 有助于各种大脑疾病的病理生理学，如认知能力下降 和癫痫。这些实验的具体目的主要集中在抑制方面。 含γ-氨基丁酸的突触传递 正常脑内抑制性中间神经元及其3个潜在和普遍突起的调节 大脑皮层和创伤后癫痫发生的模型。这些神经元是 已知易受伤害。具体目标涉及(1)发射机释放的控制 突触前钙通道和(2，3)对GABA能抑制的调制作用 神经肽Y和GABA在其受体和选择性钙离子作用下产生的 主要类抑制性中间神经元突触前终末上的电流阻滞剂。 所采用的技术包括使用全细胞膜片钳记录自发的 并诱发由识别的亚类产生的抑制性突触后电流(IPSCs 在体外脑片中的中间神经元；激光扫描光刺激标测大脑皮质 连通性；配对录音以检查从中间神经元到其他神经元的单一IPSCs 中间神经元和锥体细胞；使用带有GFP标记的基因工程小鼠 特定中间神经元种类；受体激动剂的局部应用或沐浴灌流 和敌手。部分皮质隔离模型将用于慢性提供 损伤、致痫的新皮质脑片，并评估这些突触前的变化 可能导致过度兴奋的调节机制。长期目标 是确定最终可能成为选择性药物靶标的关键异常 用来预防或治疗人类创伤后癫痫的药物。

Project Summary: Presynaptic mechanisms controlling excitatory and inhibitory synaptic transmission in the cerebral cortex have critical roles in normal information processing and also may contribute to the pathophysiology of a variety of brain disorders such as cognitive decline and epilepsy. The specific aims of these experiments focus primarily on inhibitory synaptic transmission mediated by gamma-amino butyric acid (GABA)-containing inhibitory interneurons and its regulation by 3 potent and ubiquitous processes in normal cerebral cortex and in a model of posttraumatic epileptogenesis. These neurons are known to be vulnerable to injury. Specific aims relate to (1) control of transmitter release by presynaptic Ca++ channels and (2,3) modulatory effects on GABAergic inhibition produced by actions of neuropeptide Y and GABA at their receptors and selective Ca++ current blockers on presynaptic terminals of major classes of inhibitory interneurons. Techniques employed include use of whole cell patch clamp recordings of spontaneous and evoked inhibitory postsynaptic currents (IPSCs) generated by identified subclasses of interneurons in in vitro brain slices; laser scanning photostimulation to map cortical connectivity; paired recordings to examine unitary IPSCs from interneurons to other interneurons and pyramidal cells; use of genetically engineered mice with GFP label in specific interneuron species; and local application or bath perfusion of receptor agonists and antagonists. The partial cortical isolation model will be used to provide chronically injured, epileptogenic neocortical slices and assess changes in these presynaptic modulatory mechanisms that might contribute to hyperexcitability. The long term goals are to identify critical abnormalities that might eventually be targets for selective agents that would used to prevent or treat human posttraumatic epilepsy.