Cysteine string protein-α is essential for the high calcium sensitivity of exocytosis in a vertebrate synapse

Cysteine string protein (CSP alpha) is a synaptic vesicle protein present in most central and peripheral nervous system synapses. Previous studies demonstrated that the deletion of CSP alpha results in postnatal sensorial and motor impairment and premature lethality. To understand the participation of CSP alpha in neural function in vertebrates, we have studied the properties of synaptic transmission of motor terminals in wild-type and CSP alpha knockout mice. Our results demonstrate that, in the absence of CSP alpha, fast Ca2+-triggered release was not affected at postnatal day (P)14 but was dramatically reduced at P18 and P30 without a change in release kinetics. Although mutant terminals also exhibited a reduction in functional vesicle pool size by P30, further analysis showed that neurotransmission could be 'rescued' by high extracellular [Ca2+] or by the presence of a phorbol ester, suggesting that an impairment in the fusion machinery, or in vesicle recycling, was not the primary cause of the dysfunction of this synapse. The specific shift to the right of the Ca2+ dependence of synchronous release, and the lineal dependence of secretion on extracellular [Ca2+] in mutant terminals after P18, suggests that CSP alpha is indispensable for a normal Ca2+ sensitivity of exocytosis in vertebrate mature synapses.