GRK5 Regulates Social Behavior Via Suppression of mTORC1 Signaling in Medial Prefrontal Cortex

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Impairments in social behaviors are features of a number of psychiatric diseases associated with subtle alterations in the medial prefrontal cortex (mPFC) circuitry. G protein-coupled receptor kinase (GRK) 5 is widely expressing in the cortex, however, its role in regulation of the mPFC activity and the development of social behaviors and psychiatric disorders is unclear. Here, we found that GRK5 dificiency in mice caused social behavior impairments. Further morphological, electrophysiological, and biochemical analyses showed abnormal postsynaptic ultrastructure, impaired excitatory synaptic transmission, the increased association of raptor with mTOR, and overactivated mTORC1-S6K signaling in the mPFC of <span style="font-style:italic;">Grk5</span>^{<span style="font-style:italic;">−/−</span>} mice. Conditional knockdown of GRK5 in the mPFC caused impairments in social interaction and social novelty recognition behaviors; whereas selectively overexpressing GRK5 in the mPFC of <span style="font-style:italic;">Grk5</span>^{<span style="font-style:italic;">−/−</span>} mice rescued the social novelty recognition phenotype. Inhibition of the overactivated mTORC1-S6K signaling pathway by rapamycin or mGluR5 antagonist ameliorated the deficiency of the excitatory synaptic transmission in the mPFC and the social recognition of <span style="font-style:italic;">Grk5</span>^{<span style="font-style:italic;">−/−</span>} mice. These results indicate that GRK5 is critical for maintaining normal mTORC1 signaling and connectivity in mPFC, and normal social behavior.</span>

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