SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release.
SV2 proteins are abundant synaptic vesicle proteins expressed in two major (SV2A and SV2B) and one minor isoform (SV2C) that resemble transporter proteins. We now show that SV2B knockout mice are phenotypically normal while SV2A- and SV2A/SV2B double knockout mice exhibit severe seizures and die postnatally. In electrophysiological recordings from cultured hippocampal neurons, SV2A- or SV2B-deficient cells exhibited no detectable abnormalities. Neurons lacking both SV2 isoforms, however, experienced sustained increases in Ca2+-dependent synaptic transmission when two or more action potentials were triggered in succession. These increases could be reversed by EGTA-AM. Our data suggest that without SV2 proteins, presynaptic Ca2+ accumulation during consecutive action potentials causes abnormal increases in neurotransmitter release that destabilize synaptic circuits and induce epilepsy.
Janz
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Howard Hughes Medical Institute, Center for Basic Neuroscience and Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas 75235, USA.
Goda
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Geppert
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Missler
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Südhof
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TC
D000818:Animals; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D003001:Cloning, Molecular; D004533:Egtazic Acid / Q000494:pharmacology; D004594:Electrophysiology; D004705:Endocytosis / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D005091:Exons; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007438:Introns; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology; D013569:Synapses / Q000502:physiology; D015431:Weight Loss / Q000502:physiology
D002614:Chelating Agents; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C489614:Sv2a protein, mouse; D004533:Egtazic Acid