Experience-Dependent and Input-Specific Regulation of Neocortical Circuit Development by Genes Linked to Neurodevelopmental Disorders




Zhang, Zhe

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Abnormal structural and functional brain connectivity has been widely observed in human neuropsychiatric diseases. Specifically, patients with neurodevelopmental disorders like autism often show an imbalance in the local versus long-range connectivity for cerebral cortex. Whether and how genes implicated in neurodevelopmental disorders regulate development of cortical synaptic connectivity in a pathway-specific manner remain largely unknown. Furthermore, environmental sensory experience can determine or significantly remodel the postnatal development of synaptic connections and neural circuits in sensory cortices. Knowledge on what intracellular proteins or mechanisms can mediate experience-dependent development of specific cortical synaptic connections is also lacking. In this work, I studied the roles of two neurodevelopment disease implicated genes, namely, fragile X mental retardation 1 (Fmr1) and myocyte enhancer factor 2c (Mef2c) in the postnatal experience-dependent development of input-specific synaptic connections. I report that postnatal, cell-autonomous deletion of Fmr1 in postsynaptic L2/3 or L5 neurons results in a selective weakening of AMPA receptor-, but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. Unlike callosal inputs, synapses originating from local L4 and L2/3 circuits are normal with postsynaptic Fmr1 deletion, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. Opposite to Fmr1 KO, postnatal deletion of Mef2c in L2/3 neurons leads to a cell autonomous and selective weakening of excitatory synapses from L4, whereas ipsilateral or contralateral long-range excitatory synaptic inputs are unaffected. Postsynaptic Mef2c only promotes the development but not the maintenance of L4-to-L2/3 excitatory synaptic connections and Fmr1 is not required for this process, in contrast to predictions from work in CA1 hippocampal neurons. Weakening of L4-L2/3 synaptic strength by sensory deprivation can be rescued by postnatal postsynaptic expression of a transcriptionally active form of MEF2C (MEF2-VP16), suggesting that MEF2C transcriptional activation drives experience-dependent development of L4-L2/3 synapses. Together, my findings on Fmr1 and Mef2c demonstrate an interaction of experience and gene functions in regulation of specific synaptic connections with important implications for neurodevelopmental disorders.

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