Loss of retinoid X receptor gamma subunit impairs group 1 mGluR mediated electrophysiological responses and group 1 mGluR dependent behaviors

Abstract Retinoid X receptors are members of the nuclear receptor family that regulate gene expression in response to retinoic acid and related ligands. Group 1 metabotropic glutamate receptors are G-protein coupled transmembrane receptors that activate intracellular signaling cascades in response to the neurotransmitter, glutamate. These two classes of molecules have been studied independently and found to play important roles in regulating neuronal physiology with potential clinical implications for disorders such as depression, schizophrenia, Parkinson’s and Alzheimer’s disease. Here we show that mice lacking the retinoid X receptor subunit, RXRγ, exhibit impairments in group 1 mGluR-mediated electrophysiological responses at hippocampal Schaffer collateral-CA1 pyramidal cell synapses, including impaired group 1 mGluR-dependent long-term synaptic depression (LTD), reduced group 1 mGluR-induced calcium release, and loss of group 1 mGluR-activated voltage-sensitive currents. These animals also exhibit impairments in a subset of group 1 mGluR-dependent behaviors, including motor performance, spatial object recognition, and prepulse inhibition. Together, these observations demonstrate convergence between the RXRγ and group 1 mGluR signaling pathways that may function to coordinate their regulation of neuronal activity. They also identify RXRγ as a potential target for the treatment of disorders in which group 1 mGluR signaling has been implicated.