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

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 neocorte...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2021-10, Vol.37 (2), p.109805-109805, Article 109805
Main Authors: Fernandes, Giselle, Mishra, Pradeep K., Nawaz, Mohammad Sarfaraz, Donlin-Asp, Paul G., Rahman, Mohammed Mostafizur, Hazra, Anupam, Kedia, Sonal, Kayenaat, Aiman, Songara, Dheeraj, Wyllie, David J.A., Schuman, Erin M., Kind, Peter C., Chattarji, Sumantra
Format: Article
Language:English
Subjects:
amygdala
Animals
autism spectrum disorders
Basolateral Nuclear Complex - metabolism
Basolateral Nuclear Complex - physiopathology
Behavior, Animal
Disease Models, Animal
Fear
fear learning
Fragile X Mental Retardation Protein - genetics
Fragile X Mental Retardation Protein - metabolism
Fragile X Syndrome
Fragile X Syndrome - genetics
Fragile X Syndrome - metabolism
Fragile X Syndrome - physiopathology
Fragile X Syndrome - psychology
long-term potentiation
Male
Mental Recall
mGluR5
Neuronal Plasticity
presynaptic
Rats
Rats, Sprague-Dawley
Rats, Transgenic
Receptor, Metabotropic Glutamate 5 - metabolism
synaptic plasticity
Synaptic Transmission
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Summary: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. [Display omitted] •Recall of conditioned fear is deficient in a rat model of fragile X syndrome•Synaptic transmission, and plasticity underlying fear learning, is reduced in the BLA•mGluR5 receptors are present in presynaptic terminals of the BLA•Activation of BLA mGluR5 restores synaptic plasticity and fear learning in FXS rats Fernandes et al. investigate the synaptic basis of deficient conditioned fear and its reversal in FXS rats. They find presynaptic mGluR5 in the amygdala, activation of which restores normal synaptic transmission, plasticity, and fear learning. This highlights the importance of circuit-specific differences in FXS pathophysiology and mGluR-based therapeutic strategies.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.109805