Correction of amygdalar dysfunction in a rat model of fragile X syndrome.

Giselle Fernandes,Pradeep K Mishra,Erin M Schuman,Sumantra Chattarji,Sonal Kedia,Mohammed Mostafizur Rahman,Peter C Kind,Aiman Kayenaat,Paul G Donlin-Asp,Mohammad Sarfaraz Nawaz,Anupam Hazra,David J.A Wyllie,Dheeraj Songara

doi:10.1016/j.celrep.2021.109805

Abstract

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of invitro and invivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology.

Highlights

Fragile X syndrome (FXS), a leading genetic cause of intellectual disability and autism spectrum disorder, is caused by the absence of the fragile X mental retardation protein (FMRP) produced by the fragile X mental retardation1 (FMR1) gene
A major observation leading to this theory is that mGluR5 is involved in long-term depression (LTD) (Fitzjohn et al, 2001; Palmer et al, 1997), a form of hippocampal synaptic plasticity that is elevated in the Fmr1 knockout (Fmr1À/y) mouse (Hou et al, 2006; Huber et al, 2002; Nakamoto et al, 2007; Till et al, 2015)
Would the metabotropic glutamate receptors (mGluRs) theory of FXS hold in the amygdala despite the divergent patterns of plasticity defects seen in this brain area? The aim of the present study is to address these questions at multiple levels of neural organization in the amygdala of a rat model of FXS

Summary

Introduction

Fragile X syndrome (FXS), a leading genetic cause of intellectual disability and autism spectrum disorder, is caused by the absence of the fragile X mental retardation protein (FMRP) produced by the fragile X mental retardation (FMR1) gene. A major observation leading to this theory is that mGluR5 is involved in long-term depression (LTD) (Fitzjohn et al, 2001; Palmer et al, 1997), a form of hippocampal synaptic plasticity that is elevated in the Fmr knockout (Fmr1À/y) mouse (Hou et al, 2006; Huber et al, 2002; Nakamoto et al, 2007; Till et al, 2015) This is significant in light of the contrasting nature of mGluR-dependent synaptic plasticity in the hippocampus versus amygdala. An mGluR-antagonist failed to reverse deficient amygdalar LTP in Fmr1À/y mice (Suvrathan et al, 2010) These observations underscore the need to modify the current mGluR-based framework to better explain FXS-related synaptic dysfunction in the amygdala

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