Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel

George K. E. Umanah, Marco Pignatelli, Xiling Yin, Rong Chen, Joshua Crawford, Stewart Neifert, Leslie Scarffe, Adam A. Behensky, Noah Guiberson, Melissa Chang, Erica Ma, Jin Wan Kim (+11 others)
2017 Science Translational Medicine  
The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in
more » ... se primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration-approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.
doi:10.1126/scitranslmed.aah4985 pmid:29237760 fatcat:chmh3kbhrfgbvpvc2pkyynzj2y