Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming

doi:10.1073/pnas.122623799

Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming

^*Max-Planck-Institute for Experimental Medicine, Department of Molecular Neurobiology, D-37075 Göttingen, Germany; and ^‡Max-Planck-Institute for Biophysical Chemistry, Department of Membrane Biophysics, D-37077 Göttingen, Germany

Edited by Erwin Neher, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany, and approved April 18, 2002 (received for review November 23, 2001)

Abstract

Synaptic vesicles must be primed to fusion competence before they can fuse with the plasma membrane in response to increased intracellular Ca²⁺ levels. The presynaptic active zone protein Munc13-1 is essential for priming of glutamatergic synaptic vesicles in hippocampal neurons. However, a small subpopulation of synapses in any given glutamatergic nerve cell as well as all γ-aminobutyratergic (GABAergic) synapses are largely independent of Munc13-1. We show here that Munc13-2, the only Munc13 isoform coexpressed with Munc13-1 in hippocampus, is responsible for vesicle priming in Munc13-1 independent hippocampal synapses. Neurons lacking both Munc13-1 and Munc13-2 show neither evoked nor spontaneous release events, yet form normal numbers of synapses with typical ultrastructural features. Thus, the two Munc13 isoforms are completely redundant in GABAergic cells whereas glutamatergic neurons form two types of synapses, one of which is solely Munc13-1 dependent and lacks Munc13-2 whereas the other type employs Munc13-2 as priming factor. We conclude that Munc13-mediated vesicle priming is not a transmitter specific phenomenon but rather a general and essential feature of multiple fast neurotransmitter systems, and that synaptogenesis during development is not dependent on synaptic secretory activity.

Footnotes

↵ † F.V., A.S., J.-S.R., and N.B. contributed equally to this work.
↵ § To whom reprint requests should be addressed. E-mail: reim{at}em.mpg.de or crosenm{at}gwdg.de.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

KO,

knockout;

DKO,

double knockout;

GABAergic,

γ-aminobutyratergic;

DIV,

days in vitro;

E18,

embryonic day 18;

mEPSC,

miniature excitatory postsynaptic current;

mIPSC,

miniature inhibitory postsynaptic currents;

MAP-2,

microtubule-associated protein-2