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

点击翻译按钮获取中文摘要

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.