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Stimulation of synaptic vesicle exocytosis by the mental disease gene DISC1 is mediated by N-Type voltage-gated calcium channels

Stimulation of synaptic vesicle exocytosis by the mental disease gene DISC1 is mediated by N-Type voltage-gated calcium channels

Tang, Willcyn, Thevathasan, Jervis Vermal, Lin, Qingshu, Lim, Kim Buay, Kuroda, Keisuke, Kaibuchi, Kozo, Bilger, Marcel, Soong, Tuck Wah and Fivaz, Marc ORCID: 0000-0003-1003-7934 (2016) Stimulation of synaptic vesicle exocytosis by the mental disease gene DISC1 is mediated by N-Type voltage-gated calcium channels. Frontiers in Synaptic Neuroscience, 8:15. ISSN 1663-3563 (Online) (doi:https://doi.org/10.3389/fnsyn.2016.00015)

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Abstract

Lesions and mutations of the DISC1 (Disrupted-in-schizophrenia-1) gene have been linked to major depression, schizophrenia, bipolar disorder and autism, but the influence of DISC1 on synaptic transmission remains poorly understood. Using two independent genetic approaches-RNAi and a DISC1 KO mouse-we examined the impact of DISC1 on the synaptic vesicle (SV) cycle by population imaging of the synaptic tracer vGpH in hippocampal neurons. DISC1 loss-of-function resulted in a marked decrease in SV exocytic rates during neuronal stimulation and was associated with reduced Ca(2+) transients at nerve terminals. Impaired SV release was efficiently rescued by elevation of extracellular Ca(2+), hinting at a link between DISC1 and voltage-gated Ca(2+) channels. Accordingly, blockade of N-type Cav2.2 channels mimics and occludes the effect of DISC1 inactivation on SV exocytosis, and overexpression of DISC1 in a heterologous system increases Cav2.2 currents. Collectively, these results show that DISC1-dependent enhancement of SV exocytosis is mediated by Cav2.2 and point to aberrant glutamate release as a probable endophenotype of major psychiatric disorders.

Item Type: Article
Additional Information: Copyright © 2016 Tang, Thevathasan, Lin, Lim, Kuroda, Kaibuchi, Bilger, Soong and Fivaz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords: synaptic vesicle cycle, neurotransmitter, synaptic transmission, DISC1, neuropsychiatric disorders
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > Department of Life & Sports Sciences
Last Modified: 16 May 2019 12:07
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: GREAT d
Selected for GREAT 2019: GREAT 3
URI: http://gala.gre.ac.uk/id/eprint/17883

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