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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, our 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 observed that activation, rather than inhibition,
of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibited deficient recall of
auditory conditioned fear, which was accompanied by a range of in vitro and in vivo deficits in synaptic transmission and
plasticity. Our analysis revealed presynaptic mGluR5 in the amygdala, activation of which reversed 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. |