Thorase variants cause defects in glutamatergic signaling and behavioral deficits: rescue by Perampanel

The AAA+ ATPase, Thorase, plays a critical role in controlling synaptic plasticity, learning and memory through regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR). Here, by sequencing a cohort of schizophrenia patients we identify Thorase rare variants (TRV) that cause defects in glutamatergic signaling through impairment in AMPAR internalization, recycling and function. Internalization of AMPAR is significantly reduced in neurons expressing TRVs, leading to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Furthermore, these defects lead to mouse behavioral deficits in schizophrenia-like models and importantly these impairments are rescued by the competitive AMPAR antagonist, perampanel. These findings suggest that Thorase could be an important mediator of symptoms associated with schizophrenia-like behaviors, and support the FDA approved AMPAR antagonist perampanel as a potential treatment strategy for patients with compromised AMPAR-mediated glutamatergic neurotransmission.