Dataset Information

Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling.

ABSTRACT: Schizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8^A391T) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8^A391T mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8^WT) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1? protein expression, and increased NF?B following TNF? stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.

SUBMITTER: Tseng WC

PROVIDER: S-EPMC7895948 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling.

Tseng Wei Chou WC Reinhart Veronica V Lanz Thomas A TA Weber Mark L ML Pang Jincheng J Le Kevin Xuong Vinh KXV Bell Robert D RD O'Donnell Patricio P Buhl Derek L DL

Translational psychiatry 20210219 1

Schizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8<sup>A391T</sup>) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8<sup>A391T</sup> mutation resulted in reduced zi ...[more]

PMID: 33608496

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Dataset Information

Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling.

Publications

Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling.

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