Experience-Dependent Plasticity of Neocortical Inhibitory Networks

描述(申请人提供)：这项研究的长期目标是了解新皮质抑制电路的形成机制，通过这些机制，新皮质抑制电路能够适应来自外围感觉器官的感觉输入，并保持它们与感觉皮质中的皮质兴奋电路的平衡。在大脑发育过程中，大脑皮层的神经元建立连接，然后通过经验依赖的机制进行微调。虽然关于谷氨酸能神经网络形成的谷氨酸能神经突触的成熟和活性依赖性修饰的过程已知很多，但新皮质GABA能突触的出生后发育及其在活性依赖性修饰中的作用仍不清楚。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。新大脑皮层兴奋和抑制之间的平衡失调会引发异常活动，如癫痫发作。这一建议检验的中心假设是，抑制性中间神经元中谷氨酸能突触的长期可塑性在经验依赖的神经元间网络的完善中发挥着重要作用。这项拟议的研究将结合电生理记录、药理学操作和定量免疫组织学分析来检查皮层内抑制网络依赖经验成熟的潜在机制。支持皮质可塑性的突触强度将通过绿色荧光蛋白标记的中间神经元来测量，这些中间神经元来自转基因小鼠的脑片，其中的胡须体验在出生后发生了变化。这种方法允许在体外记录的皮质内突触可塑性与体内先前的感觉经验之间建立联系。这项研究的成功完成将为我们提供一个全面的视角，了解感觉经验在生命早期形成抑制性突触连接中的作用，以及兴奋和抑制平衡的潜在机制。这一信息可能有助于开发新的治疗策略，用于治疗由于新皮质主神经元和中间神经元之间的异常连接而导致的发育性神经和精神障碍。

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.