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

Cell Rep. 2021 Oct 12;37(2):109805. doi: 10.1016/j.celrep.2021.109805.


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 in vitro and in vivo 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.

Keywords: Fragile X Syndrome; amygdala; autism spectrum disorders; fear learning; long-term potentiation; mGluR5; presynaptic; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basolateral Nuclear Complex / metabolism
  • Basolateral Nuclear Complex / physiopathology*
  • Behavior, Animal*
  • Disease Models, Animal
  • Fear*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / physiopathology*
  • Fragile X Syndrome / psychology
  • Male
  • Mental Recall*
  • Neuronal Plasticity*
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Synaptic Transmission*


  • Fmr1 protein, rat
  • Grm5 protein, rat
  • Receptor, Metabotropic Glutamate 5
  • Fragile X Mental Retardation Protein