| Literature DB >> 29237760 |
George K E Umanah1,2, Marco Pignatelli3, Xiling Yin1,2, Rong Chen1,2, Joshua Crawford4, Stewart Neifert1,2, Leslie Scarffe1,2,5, Adam A Behensky1,2, Noah Guiberson1,2, Melissa Chang5, Erica Ma6, Jin Wan Kim7, Cibele C Castro1,8, Xiaobo Mao1,2, Li Chen1,2, Shaida A Andrabi1,2, Mikhail V Pletnikov4, Ann E Pulver4, Dimitrios Avramopoulos4,9, Antonello Bonci3,4, David Valle9,10, Ted M Dawson11,2,5,12, Valina L Dawson11,2,5,13.
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.Entities:
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Year: 2017 PMID： 29237760 PMCID： PMC6573025 DOI： 10.1126/scitranslmed.aah4985
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956