Dynamic control of presynaptic function in health and disease

The process of synaptic vesicle priming is a key determinant of synapse strength and plasticity because it maintains a pool of readily releasable vesicles at any given time and determines the time course of synaptic fatigue and recovery, e.g. upon exhaustion of readily releasable vesicles during and after phases of high synaptic activity. The corresponding forms of synaptic short-term plasticity determine multiple complex brain functions, from sensory adaptation to working memory. Munc13s execute synaptic vesicle priming by regulating the assembly of fusogenic SNARE complexes. Munc13s are regulated by three major pathways, involving (i) calcium-calmodulin signaling via dedicated amphipathic calcium-calmodulin binding sites, (ii) diacylglycerol signaling via C1 domains, and (iii) calcium-phospholipid signaling via C2 domains. We studied the functional relevance of these regulatory pathways in various synapse types and found that calcium-dependent Munc13-regulating pathways are major determinants of synaptic short-term plasticity, synapse endurance, and synaptic fidelity. I will discuss these data in the context (i) of the combined role of signaling pathways that target presynaptic function, (ii) of the role of Munc13 priming proteins in determining the unique features of regulated exocytosis at nerve cells synapses, and (iii) of the role of Munc13 mutations in neuropsychiatric disorders.