Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A)

Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A)

Departments of ^*Pharmacology and ^‡Psychology, University of Washington, Seattle, WA 98195; and ^§Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305

Communicated by William A. Catterall, University of Washington School of Medicine, Seattle, WA (received for review September 13, 1999)

Abstract

Synaptic vesicle protein 2 (SV2) is a membrane glycoprotein common to all synaptic and endocrine vesicles. Unlike many proteins involved in synaptic exocytosis, SV2 has no homolog in yeast, indicating that it performs a function unique to secretion in higher eukaryotes. Although the structure and protein interactions of SV2 suggest multiple possible functions, its role in synaptic events remains unknown. To explore the function of SV2 in an in vivo context, we generated mice that do not express the primary SV2 isoform, SV2A, by using targeted gene disruption. Animals homozygous for the SV2A gene disruption appear normal at birth. However, they fail to grow, experience severe seizures, and die within 3 weeks, suggesting multiple neural and endocrine deficits. Electrophysiological studies of spontaneous inhibitory neurotransmission in the CA3 region of the hippocampus revealed that loss of SV2A leads to a reduction in action potential-dependent γ-aminobutyric acid (GABA)ergic neurotransmission. In contrast, action potential-independent neurotransmission was normal. Analyses of synapse ultrastructure suggest that altered neurotransmission is not caused by changes in synapse density or morphology. These findings demonstrate that SV2A is an essential protein and implicate it in the control of exocytosis.

Footnotes

↵ † K.M.C., J.M.G., and T.A.J. contributed equally to this work.
↵ ¶ To whom reprint requests should be addressed at: Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195. E-mail: bajjalie{at}u.washington.edu.
Abbreviations:

SV2,

synaptic vesicle protein 2;

Pn,

postnatal day n;

GABA,

γ-aminobutyric acid;

IPSCs,

inhibitory postsynaptic currents;

mIPSCs,

miniature IPSCs;

sIPSCs,

spontaneous IPSCs;

CNS,

central nervous system;

APV,

2-amino-5-phosphonovaleric acid;

CNQX,

6-cyano-7-nitroquinoxaline-2,3-dione