Modulation of Neocortical Interneuronal Function

项目摘要： 神经元兴奋性和抑制性突触传递的突触前机制 大脑皮层在正常的信息处理中起着关键作用， 导致各种脑部疾病的病理生理学， 和癫痫。这些实验的具体目的主要集中在抑制 含γ-氨基丁酸（GABA）的突触传递 抑制性中间神经元及其通过3种有效和普遍存在的过程的调节 大脑皮层和创伤后癫痫发生模型。这些神经元 很容易受伤具体目标涉及（1）控制发射器释放 突触前Ca ~（++）通道和（2，3）对GABA能抑制的调节作用 由神经肽Y和GABA在其受体上的作用和选择性Ca++产生 抑制性中间神经元的主要类别的突触前末梢上的电流阻断剂。 所采用的技术包括使用全细胞膜片钳记录自发性 和由识别的亚类产生的诱发抑制性突触后电流（IPSC） 体外脑切片中的中间神经元;激光扫描光刺激以映射皮层 连接性;配对记录以检查从中间神经元到其他神经元的单一IPSC 中间神经元和锥体细胞;具有GFP标记基因工程小鼠在 特定的中间神经元种类;和受体激动剂的局部应用或浴灌注 和拮抗剂。部分皮层隔离模型将用于提供慢性 损伤的致癫痫新皮层切片，并评估这些突触前 调节机制，可能有助于过度兴奋。长期目标 是为了识别可能最终成为选择性药物靶点的关键异常 用于预防或治疗人类创伤后癫痫。

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.