The role of AMPA receptors in critical period plasticity in the auditory cortex

神经系统的最佳功能包括在生命早期的关键期(CP)对神经元回路进行适当的依赖活动的精炼。这些时期的特点是最高水平的突触可塑性，快速学习，突触形成以及对神经元连接的持久影响。目前，CP可塑性的细胞和分子机制仍然不清楚，尽管流行的观点是微调的局部兴奋/抑制平衡决定了CP的可塑性。小白蛋白阳性抑制中间神经元的抑制成熟与感觉可塑性CPS的形成有关。然而，不同感觉图中抑制回路的成熟是通过谷氨酸能兴奋来实现的。到目前为止，关于谷氨酸能兴奋在未成熟大脑中CP可塑性调节中的作用的详细了解还很少。听觉皮质的CP可塑性与脑功能发育和认知功能密切相关。这一应用的中心假设是，锥体神经元和小白蛋白阳性抑制中间神经元中谷氨酸受体的成熟，特别是AMPA受体(AMPAR)，通过调节听觉皮质的张力映射可塑性，决定了CP的时机和持续时间。为了验证这一假设，我们将首先表征与听觉皮质中CP计时相关的锥体神经元和小白蛋白阳性抑制中间神经元中AMPAR表达和功能的发育变化。然后，我们将研究锥体神经元和小白蛋白阳性抑制性中间神经元中仅有NMDAR的沉默突触成熟是否决定了听觉皮质中CP的可塑性。最后，我们打算通过研究阻断AMPAR功能的后果来评估AMPAR成熟在听皮质CP区锥体神经元和中间神经元中的因果作用。我们的研究计划将为理解听觉皮质中CP纯音定位可塑性的细胞基础提供关键信息。这将有助于识别调节这些神经发育过程的候选分子位点。整个研究计划的HQP培训将有助于培养高技能人才，为在学术、工业和政府职业中成功的职业生涯做好准备。**

The optimal functioning of the nervous system involves proper activity-dependent refinement of neuronal circuits during critical periods (CPs) in early life. Such periods are characterized by highest level of synaptic plasticity, rapid learning, synaptogenesis as well as enduring consequences for neuronal connectivity. Currently, the cellular and molecular mechanisms of CP plasticity remain elusive, although the prevailing notion is that the finely tuned local excitatory/inhibitory balance determines the CP plasticity. The maturation of inhibition from parvalbumin-positive inhibitory interneuron has been implicated in the formation of CPs for sensory plasticity. However, the maturation of inhibitory circuits in various sensory maps develops through glutamatergic excitation. To date, detailed knowledge about the role of glutamatergic excitation in the regulation of CP plasticity in the immature brain is sparse. The CP plasticity of the auditory cortex has been strongly implicated in both functional brain development and cognitive function. The central hypothesis of this application is that the maturation of glutamate receptors in both pyramidal neurons and parvalbumin-positive inhibitory interneurons, in particular AMPA receptors (AMPAR), critically determines the timing and the duration of CP through regulating tonotopic-mapping plasticity in the auditory cortex. To test this hypothesis, we will first characterize the developmental changes in AMPAR expression and function in both pyramidal neurons and parvalbumin-positive inhibitory interneurons related to CP timing in the auditory cortex. Then we will examine whether NMDAR-only silent synapse maturation in pyramidal neurons and parvalbumin-positive inhibitory interneurons determines CP tonotopic plasticity in the auditory cortex. Finally, we intend to assess the causal roles of AMPAR maturation in pyramidal neurons and interneurons in the CP of the auditory cortex by studying the consequence of blocking AMPARs function. Our research program will provide critical information for understanding the cellular underpinnings of the CP tonotopic mapping plasticity in the auditory cortex. This will facilitate the identification of candidate molecular sites for modulating these neurodevelopmental processes. The HQP training throughout this research program will aid in the development of highly skilled personnel equipped for successful careers in academic, industrial, and government professions. **