TY - JOUR
T1 - Stimulation of synaptic vesicle exocytosis by the mental disease gene DISC1 is mediated by N-type voltage-gated calcium channels
AU - Tang, Willcyn
AU - Thevathasan, Jervis Vermal
AU - Lin, Qingshu
AU - Lim, Kim Buay
AU - Kuroda, Keisuke
AU - Kaibuchi, Kozo
AU - Bilger, Marcel
AU - Soong, Tuck Wah
AU - Fivaz, Marc
N1 - Publisher Copyright:
� 2016 Tang, Thevathasan, Lin, Lim, Kuroda, Kaibuchi, Bilger, Soong and Fivaz.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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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U2 - 10.3389/fnsyn.2016.00015
DO - 10.3389/fnsyn.2016.00015
M3 - Article
AN - SCOPUS:84994047716
SN - 1663-3563
VL - 8
JO - Frontiers in Synaptic Neuroscience
JF - Frontiers in Synaptic Neuroscience
IS - JUN
M1 - 15
ER -