title: Stimulation of Synaptic Vesicle Exocytosis by the Mental Disease Gene DISC1 is Mediated by N-Type Voltage-Gated Calcium Channels.
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.
authors.affiliation: DUKE-NUS Medical School, Program in Neuroscience and Behavioral Disorders Singapore, Singapore.
authors.forename: Willcyn
authors.initials: W
authors.lastname: Tang
authors.affiliation: DUKE-NUS Medical School, Program in Neuroscience and Behavioral Disorders Singapore, Singapore.
authors.forename: Jervis Vermal
authors.initials: JV
authors.lastname: Thevathasan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
authors.forename: Qingshu
authors.initials: Q
authors.lastname: Lin
authors.affiliation: DUKE-NUS Medical School, Program in Neuroscience and Behavioral Disorders Singapore, Singapore.
authors.forename: Kim Buay
authors.initials: KB
authors.lastname: Lim
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine Nagoya, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuroda
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine Nagoya, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: DUKE-NUS Medical School, Program in Health Services and Systems Research Singapore, Singapore.
authors.forename: Marcel
authors.initials: M
authors.lastname: Bilger
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
authors.forename: Tuck Wah
authors.initials: TW
authors.lastname: Soong
authors.affiliation: DUKE-NUS Medical School, Program in Neuroscience and Behavioral DisordersSingapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.
authors.forename: Marc
authors.initials: M
authors.lastname: Fivaz
keywords: DISC1; glutamate; hippocampus; neurotransmitter; psychiatric disorders; schizophrenia; synaptic vesicle release