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 prot eins. We now show that SV2B knockout mice are phenotypically normal while S V2A- and SV2A/SV2B double knockout mice exhibit severe seizures and die pos tnatally. In electrophysiological recordings from cultured hippocampal neur ons, SV2A- or SV2B-deficient cells exhibited no detectable abnormalities. N eurons 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 neurotran smitter release that destabilize synaptic circuits and induce epilepsy.