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Accueil > Agenda > Les séminaires Jean Roche > Synapse formation : specificity and dependence upon synaptic (...)

Synapse formation : specificity and dependence upon (...)

Lundi 12 septembre 2005, 11h, salle Lissitzky.


1 : Mol Cell Biol. 2005 Jul ;25(14):5973-84.

Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse.

Varoqueaux F, Sons MS, Plomp JJ, Brose N.

Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, Hermann-Rein Str. 3, D-37075 Gottingen, Germany. varoqueaux

In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and gamma-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously : i.e., without dedicated priming proteins in the release machinery.

2 : Eur J Cell Biol. 2004 Sep ;83(9):449-56.

Neuroligin 2 is exclusively localized to inhibitory synapses.

Varoqueaux F, Jamain S, Brose N.

Max-Planck-Institute for Experimental Medicine, Department of Molecular Neurobiology, Gottingen, Germany.

Neuroligins are cell adhesion proteins that are thought to instruct the formation and alignment of synaptic specializations. The three known rodent neuroligin isoforms share homologous extracellular acetylcholinesterase-like domains that bridge the synaptic cleft and bind beta-neurexins. All neuroligins have identical intracellular C-terminal motifs that bind to PDZ domains of various target proteins. Neuroligin 1 is specifically localized to glutamatergic postsynaptic specializations. We show here that neuroligin 2 is exclusively localized to inhibitory synapses in rat brain and dissociated neurons. In immature neurons, neuroligin 2 is found at synapses and also at GABAA receptor aggregates that are not facing presynaptic termini, indicating that postsynaptic mechanisms lead to synaptic recruitment of neuroligin 2. Our findings identify neuroligin 2 as a new cell adhesion protein specific for inhibitory synapses and open new avenues for identifiying the constituents of this unique type of postsynaptic specialization.

3 : Proc Natl Acad Sci U S A. 2002 Jun 25 ;99(13):9037-42. Epub 2002 Jun 17.

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

Varoqueaux F, Sigler A, Rhee JS, Brose N, Enk C, Reim K, Rosenmund C.

Max-Planck-Institute for Experimental Medicine, Department of Molecular Neurobiology, D-37075 Gottingen, Germany.

Synaptic vesicles must be primed to fusion competence before they c an 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 gamma-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.

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