ReportsNeuroscience

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

See allHide authors and affiliations

Science Translational Medicine  13 Dec 2017:
Vol. 9, Issue 420, eaah4985
DOI: 10.1126/scitranslmed.aah4985

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Thorase ATPase, a multifunctional enzyme

Alterations in glutamatergic neurotransmission are thought to contribute to schizophrenia, a neuropsychiatric disease with multifactorial causes. Umanah et al. identified variants in the AAA+ ATPase Thorase in several patients with schizophrenia. They show in vitro that these variants disrupted the expression of glutamate receptors, altering their physiological function in mouse primary cortical neurons. Mice expressing these variants exhibited behavioral deficits. An FDA-approved drug, Perampanel, rescued these behavioral deficits, suggesting that Perampanel may be useful for treating diseases involving aberrant glutamatergic neurotransmission.

Abstract

The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-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 mouse 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.

View Full Text