<i>Grin2b</i>-mutant mice exhibit heightened remote fear via suppressed extinction and chronic amygdalar synaptic and neuronal dysfunction.

Abstract

Individuals with autism spectrum disorders (ASD) frequently show long-lasting traumatic fear memory, but the underlying mechanisms remain unclear. Here, we report that <i>Grin2b</i>-mutant mice carrying a human ASD-risk mutation (<i>Grin2b</i>^C456Y/+ mice) show normal acquisition of contextual fear memory but suppressed fear memory extinction and enhanced remote fear memory responses, along with anxiety- and social-related abnormalities. After footshock and fear extinction, these mutants chronically develop occluded neuronal activation in the basal amygdala (BA) detectable at remote fear memory retrieval, which involves suppressed spontaneous excitatory synaptic transmission and neuronal excitability. Chemogenetic activation of mutant BA neurons during fear extinction improves fear memory extinction and remote fear memory responses without affecting anxiety- or social-related phenotypes. This rescue involves normalized spontaneous excitatory synaptic transmission and neuronal excitability. These results suggest that <i>Grin2b</i>^C456Y/+ mice, through impaired fear memory extinction, chronically develop suppressed spontaneous excitatory synaptic transmission and neuronal excitability in BA neurons that enhances remote fear memory responses.