Synapse vesicle cycle

Some neurons can fire several hundred times per second, secreting neurotransmitter each time. Synapses are remarkable secretion machines destined to undergo millions of repeated exocytic cycles in their lifetime. So how does this process work so fast and so efficiently Answers have gradually emerged from the work of many different laboratories and model systems [73, 74]. An exhaustive description is beyond the scope of this chapter, but a summary of key events and specializations of the synaptic vesicle cycle is useful. This will show how synaptic transmission is optimized spatially and biochemically (see also Chs 6,10 and 22). 

Those vesicles have been primed by docking at the active zone and are therefore ready for exocytosis upon arrival of an action potential. However, for the synapse to respond rapidly and repeatedly under heavy physiological demand, these exocytosed vesicles must be rapidly replaced. This is accomplished first from the recycled pool of vesicles and, as the demand increases, from the reserve pool. To be recycled, synaptic vesicles must be reloaded quickly after they release their contents. The sequence of events that is triggered by neurotransmitter exocytosis is known as the synaptic vesicle cycle [73,74] (Fig. 9-8). 

A synaptic vesicle cycle. The number of synaptic vesicles in a single synapse in the brain varies from fewer than 100 to several hundred. In specialized synapses there may be thousands. However, at any moment only a fraction of the total are in the "active zone," often aligned along the presynaptic membrane (Fig. 30-20A) or in specialized ribbons such as those in Fig. 30-10B. The vesicles are normally reused repeatedly, undergoing a cycle of filling with neurotransmitter, translocation to the active zone, ATP-dependent priming, exocytosis with release of the neurotransmitter into the synaptic cleft, coating with clathrin, endocytosis, and acidification as outlined in Fig. 30-20B.554-557 The entire cycle may be completed within 40-60 s to avoid depletion of active vesicles.558 559 A key event in the cycle is the arrival of an action potential at the presynaptic neuron end. 

In this chapter, we will review the evidence suggesting a role for specific synaptic vesicle-associated proteins in schizophrenia. First, we present a brief overview of the synaptic vesicle cycle in the broader context of synaptic neurotransmission at chemical synapses. We then describe the experimental evidence linking specific molecular components of the synaptic vesicle to schizophrenia. Since not all synaptic vesicle proteins have been studied in relationship to schizophrenia, this review focuses only on those proteins for which such an effort was made. Finally, we describe the potential roles these proteins could play in the context of current etiological theories of schizophrenia, and discuss the relevance of the experimental findings in the context of this enigmatic disorder. 

After the fusion of a synaptic vesicle, the RRP is refilled from the recycling pool of synaptic vesicles. For central nervous system synapses (e.g., synapses of hippocampal neurons), the recycling pool of synaptic vesicles consists of approximately 30 vesicles, approximately three to five times the number of RRP vesicles (15, 16). During repetitive synaptic stimulation, the rapid refilling of the RRP from the recycling pool sustains continuous neurotransmitter release. An overview of the synaptic vesicle cycle is shown in Fig. 1. 

Femandez-Alfonso T, Ryan TA. The efficiency of the synaptic vesicle cycle at central nervous system synapses. Trends Cell Biol. 2006 16 413-420. 

One of the consequences of this rapid increase in protein synthetic capacity in VMN neurons is that E increases the number of spines on dendrites and increases the density of synapses in the VMN. These events occur cyclically during the estrous cycle of the female rat. Dots indicate presynaptic vesicles containing neurotransmitter. 

Mozhayeva MG, Sara Y, Liu X, Kavalali ET (2002) Development of vesicle pools during maturation of hippocampal synapses. J Neurosci 22 654-65 Murthy VN, Stevens CF (1998) Synaptic vesicles retain their identity through the endocytic cycle. Nature 392 497-501... 

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