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

Chirag Upreti,Xiao-Lei Zhang,Patric K Stanton,Deqi Yin,Eric R Kandel,Russell E Nicholls,Caitlin M Woodruff,Dina S Rehanian,Zhen-Yu Zhou,Michael J Yim,Andrew M Pagano

doi:10.1038/s41598-021-84943-x

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.

Highlights

Proper control of neuronal activity and synaptic transmission is critical for normal nervous system function, and multiple neurotransmitters, neuromodulators, and signaling pathways have been found to participate in their regulation
Since long-term synaptic depression (LTD) can be induced at these synapses via at least two distinct mechanisms—one dependent on NMDA receptor activity and another dependent on group 1 metabotropic glutamate receptors (mGluRs) activity[33,34], we sought to determine whether RXRγ was required for one or both of these forms of LTD
Surprisingly—given the dependence of low-frequency dependent LTD on NMDA receptor activation[35,36] (Fig. S1)—we found that RXRγ knockout significantly impaired LTD induced by application of the group 1 mGluR agonist, DHPG (Fig. 1B), but had no Scientific Reports | (2021) 11:5552 |

Summary

Introduction

Proper control of neuronal activity and synaptic transmission is critical for normal nervous system function, and multiple neurotransmitters, neuromodulators, and signaling pathways have been found to participate in their regulation. Additional, functionally important interactions have been described between group 1 mGluRs and various downstream effectors including caveolin, norbin, prolyl-isomerase 1 (Pin1), cellular prion protein (PrPc), optineurin, and Preso[1] (reviewed in[28]) Through their various effectors, group 1 mGluRs regulate critical neuronal functions, including NMDA receptor activity, release of internal calcium, protein translation, and production of endocannabinoids. Group 1 mGluRs are required for normal homeostatic scaling of synaptic activity[29,30], for various forms of long-term synaptic potentiation (LTP), and for multiple forms of long-term synaptic depression (LTD) that, depending on synapse type, are produced via pre- or postsynaptic, protein synthesis dependent or independent, m echanisms[31,32] Given this diversity of downstream effects, it is not surprising that group 1 mGluRs have been implicated in a number of neurological and neuropsychiatric disorders including schizophrenia, depression, anxiety, autism, addiction, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and fragile X syndrome (reviewed in[24]). Together our data suggest that RXRγ is required for normal group 1 mGluR-dependent modulation of synaptic transmission and plasticity, and that these two pathways interact on the molecular level to regulate normal and disease-related nervous system function

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Conclusion