Metabolic Glutamate Receptors and p63RhoGEF Regulation of Spinogenesis and Dendritic Morphology in Layer V Pyramidal Neurons of the Prefrontal Cortex
Zukkoor, Amanda A.
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Mental retardation affects 2-3% of the total population and results in a variety of cognitive deficiencies; however, the molecular pathways involved in regulating cognition have yet to be understood. Recent studies have revealed that dendritic spines play a key role in mediating synaptic plasticity and, therefore, are important in developing cognition. A known regulator of dendritic spine structure and spinogenesis is the GTPAse RhoA, which is activated by p63RhoGEF. Upstream of this guanine exchange factor is G protein Gαq/11 which is activated by the metabolic glutamate receptors mGluR1 and mGluR5. Being upstream of RhoA, it is possible that mGluR1 and mGluR5 as well as p63RhoGEF may regulate dendritic morphology. In order to test this hypothesis, we blocked mGluR1 and mGluR5 on a cohort of transgenic mice expressing yellow fluorescent protein (YFP) in layer V pyramidal cells. Additionally, we overexpressed p63RhoGEF in young rats and analyzed spine density and dendritic morphology of layer V pyramidal cells of the prefrontal cortex. We then compared the resulting dendritic morphology to cells transfected with YFP alone. We found that blocking the metabolic glutamate receptor did not produce significant differences in spine density, and that overexpression of p63RhoGEF lead to dramatic changes in dendritic organization and structure. This suggested that other mechanisms are involved in dendritic spine regulation. We initiated development of a single neuron labeling strategy which would allow us to control for confounding factors that may alter results in the overexpression of p63RhoGEF. Future studies should uncover other pathways associated with dendritic morphology and cognition for the development of clinical treatments and therapies.