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