Unravelling the contribution of GluA3 sub-unit to mouse behavior: From autoantibodies to gene depletion

Traditionally, research on AMPA receptors has predominantly focused on GluA1 and GluA2 subunits. However, emerging consensus now emphasizes the pivotal role of GluA3 in specific forms of plasticity and behaviors. Though, most of the research conducted thus far has employed complete knockout animal model of GluA3-encoding gene (GRIA3) where compensatory events during neurodevelopment may obscure GluA3’s function.To better dissect GluA3's contribution to complex behaviors, we employed two in vivo mouse models of GluA3 downregulation in adult mice. First, we chronically administered autoantibodies directed against GluA3 sub-unit (anti-GluA3 hIgGs) into mice’s lateral ventricles. Of note, these same autoantibodies were associated to frontotemporal dementia where they contribute to the definition of a distinct sub-population of patients with unique phenotypic traits. As in the patients, also in the mouse model anti-GluA3 hIgGs interfere with GluA3 activity mediating a downregulation of GluA3 surface expression. Secondly, we employed a CRISPR-based approach to specifically deplete GluA3 in the medial prefrontal cortex (mPFC) of adult mice.Anti-GluA3 hIgGs chronic administration to mice resulted into the appearance of a peculiar phenotype, characterized by apathy and maladaptive food seeking behavior. This last aspect was most likely driven by a reduction into the activity of mPFC glutamatergic neurons projecting to Nucleus Accumbens. In addition, preliminary data from the CRISPR-based model suggest that GluA3 in the mPFC contributes to orchestrating complex behaviors.In conclusion, our findings underscore GluA3's critical role in PFC glutamatergic synapses and circuits, shedding light on its involvement in shaping specific behaviors.