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 pos...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 1999-12, Vol.24 (4), p.1003-1016
Main Authors: Janz, R, Goda, Y, Geppert, M, Missler, M, Südhof, T C
Format: Article
Language:English
Subjects:
Animals
Brain Chemistry - genetics
Brain Chemistry - physiology
Calcium Signaling - physiology
Chelating Agents - pharmacology
Cloning, Molecular
Egtazic Acid - pharmacology
Electrophysiology
Endocytosis - physiology
Exocytosis - physiology
Exons
Hippocampus - cytology
Hippocampus - physiology
Introns
Membrane Glycoproteins - genetics
Membrane Glycoproteins - physiology
Mice
Mice, Knockout
Molecular Sequence Data
Mutation
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - physiology
Neurotransmitter Agents - genetics
Neurotransmitter Agents - metabolism
Neurotransmitter Agents - physiology
Seizures - physiopathology
Synapses - physiology
Weight Loss - physiology
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Summary: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.
ISSN:0896-6273
1097-4199
DOI:10.1016/S0896-6273(00)81046-6