Quotation Tang, Willcyn, Thevathasan, Jervis Vermal, Lin, Qingshu, Lim, Kim Buay, Kuroda, Keisuke, Kaibuchi, Kozo, Bilger, Marcel, Soong, Tuck Wah, Fivaz, Marc. 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


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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 Ca2+ transients at nerve terminals. Impaired SV release was efficiently rescued by elevation of extracellular Ca2+, hinting at a link between DISC1 and voltage-gated Ca2+ 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.

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Publication's profile

Status of publication Published
Affiliation External
Type of publication Journal article
Journal Frontiers in Synaptic Neuroscience
Language English
Title Stimulation of Synaptic Vesicle Exocytosis by the Mental Disease Gene DISC1 is Mediated by N-Type Voltage-Gated Calcium Channels
Volume 8
Year 2016
Reviewed? Y
DOI http://dx.doi.org/10.3389/fnsyn.2016.00015
Open Access Y
Open Access Link https://www.frontiersin.org/articles/10.3389/fnsyn.2016.00015/full

Associations

People
Bilger, Marcel (Details)
External
Fivaz, Marc (University of Greenwich, United Kingdom)
Kaibuchi, Kozo (Nagoya University, Japan)
Kuroda, Keisuke (Nagoya University, Japan)
Lim, Kim Buay (National University of Singapore, Singapore)
Lin, Qingshu (National University of Singapore, Singapore)
Soong, Tuck Wah (National University of Singapore, Singapore)
Tang, Willcyn (Duke-NUS Medical School, Singapore)
Thevathasan, Jervis Vermal (European Molecular Biology Laboratory Heidelberg, Germany)
Organization
Health Economics and Policy Group AB (Details)
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