Experience-Dependent Plasticity of Neocortical Inhibitory Networks

描述（由申请人提供）：本研究的长期目标是了解发育中的新皮层抑制回路能够适应来自外周感觉器官的感觉输入的机制，并保持其与感觉皮层中的皮层兴奋回路的平衡。在大脑发育过程中，大脑皮层中的神经元建立连接，然后通过经验依赖机制进行微调。虽然现在已经知道了很多关于多巴胺能神经元的成熟过程和多巴胺能神经元突触网络形成的活动依赖性修饰，但新皮层GABA能神经元突触的出生后发育及其在活动依赖性修饰中的作用仍然不清楚。匹配兴奋和抑制的机制是在单个神经元和大脑回路水平上实现平衡功能的核心。新皮层兴奋和抑制之间的平衡紊乱会引起异常活动，如癫痫发作。这个建议的中心假设是，尖峰定时依赖的长期可塑性的抑制性interneurons中的神经元突触在经验依赖的细化interneurons网络中起着重要的作用。拟议的研究将利用电生理记录，药理学操作和定量免疫组织学分析相结合，以检查皮质内抑制网络的经验依赖性成熟的机制。皮层可塑性背后的突触强度将从绿色荧光蛋白标记的中间神经元中测量，中间神经元来自从转基因小鼠制备的脑切片，其中胡须经验在出生后时期被改变。这种方法允许的联系，在体外记录和以前的感觉经验在体内的皮质内突触可塑性之间的量。这项研究的成功完成将提供一个全面的观点，在塑造抑制性突触连接在生命的早期阶段和机制的兴奋和抑制平衡的感觉经验的作用。这些信息可能对开发新的治疗策略产生影响，这些策略用于治疗由新皮层主神经元和中间神经元之间异常连接引起的发育性神经和精神疾病。

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand mechanisms by which developing neocortical inhibitory circuits are able to adapt to sensory inputs from the peripheral sense organs, and to maintain their balance with the cortical excitatory circuits in the sensory cortex. During brain development, neurons in the cerebral cortex establish connections that are then fine tuned by experience-dependent mechanisms. Although much is now known regarding processes of glutamatergic maturation and activity-dependent modification of glutamatergic synapses for network formation, postnatal development of neocortical GABAergic synapses and their role in activity-dependent modification remains unclear. Mechanisms that match excitation and inhibition are central to attaining balanced function at the level of single neurons and brain circuits. Disturbances in the balance between excitation and inhibition in the neocortex provoke abnormal activities, such as epileptic seizures. The central hypothesis examined by this proposal is that the spike-timing dependent long-term plasticity of glutamatergic synapses in inhibitory interneurons plays an important role in experience-dependent refinement of interneuronal networks. The proposed research will utilize a combination of electrophysiological recording, pharmacological manipulations and quantitative immunohistological analysis to examine mechanisms underlying experience-dependent maturation of intracortical inhibitory networks. The synaptic strength underlying cortical plasticity will be measured from green-fluorescent protein labeled interneurons from brain slices prepared from transgenic mice, in which whisker experience was altered in the postnatal periods. This approach allows linkages to be made between amounts of intracortical synaptic plasticity recorded in vitro and previous sensory experiences in vivo. Successful completion of this study will provide a comprehensive view of the roles of sensory experiences in shaping inhibitory synaptic connectivity at early stages of life and mechanisms underlying excitation and inhibition balancing. This information could have implications for developing novel treatment strategies for developmental neurological and psychiatric disorders that result from aberrant connectivity among neocortical principal neurons and interneurons.