Development of Neocortical Circuits: a Cell Autonomous Examination of mGluR5 and MEF2C



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Development of neocortical circuits requires both genetic programs and sensory experience-dependent modification of synaptic function. The rules that dictate how synapses develop and respond to changing patterns of input influence both the emergence of receptive fields and the capacity for learning. In turn, the factors that determine the rules for synaptic plasticity are defined by the proteins functioning at the synapse. This project investigates two proteins situated to have wide-reaching impacts on synaptic function. One of the challenges in detailing the roles a protein plays in regulating synapses is discerning not only its acute role on synaptic function, but also its long-term impact on circuit development. Therefore, studying how a protein is engaged by physiological patterns of input in vivo over an extended period of time will provide a broader picture of how it influences synaptic function and circuit development. mGluR5 has previously been implicated in several forms of plasticity that act to directly weaken synaptic function. In this document, I provide evidence that the net-effect of mGluR5 on synaptic function throughout the first few weeks of postnatal development is to promote synaptic input pathway strength, as demonstrated in 2 prominent and well-characterized input pathways to L2/3 pyramidal cells of barrel cortex. Furthermore, I demonstrate a possible role for mGluR5 in a homeostatic mechanism, offsetting the enhanced evoked synaptic input by suppressing both spontaneous transmission and intrinsic excitability. The transcription factor MEF2 also has established roles in regulating synaptic function. However, much less is known about the synaptic mechanisms through which MEF2 mediates its effects. Here, I implicate MEF2C as the critical MEF2 family member involved in regulating synaptic function in L2/3 pyramidal cells in barrel cortex, and provide potential synaptic and molecular mechanisms by which MEF2C regulates pathway input.

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