Neurotransmitter release at synapses between nerve cells is mediated by cal
cium-triggered exocytotic fusion of synaptic vesicles'. Before fusion, vesi
cles dock at the presynaptic release site where they mature to a fusion-com
petent state(1,2). Here we identify Munc13-1, a brain-specific presynaptic
phorbol ester receptor(3,4), as an essential protein for synaptic vesicle m
aturation. We show that glutamatergic hippocampal neurons from mice lacking
Munc13-1 form ultrastructurally normal synapses whose synaptic-vesicle cyc
le is arrested at the maturation step. Transmitter release from mutant syna
pses cannot be triggered by action potentials, calcium-ionophores or hypert
onic sucrose solution. In contrast, release evoked by alpha-latrotolrin is
indistinguishable from wild-type controls, indicating that the toxin can by
pass Munc13-1-mediated vesicle maturation. A small subpopulation of synapse
s of any given glutamatergic neuron as well as all synapses of GABA (gamma-
aminobutyric acid)-containing neurons are unaffected by Munc13-1 loss, demo
nstrating the existence of multiple and transmitter-specific synaptic vesic
le maturation processes in synapses.