Synaptic vesicles are coated by synapsins, phosphoproteins that account for 9% of the vesicle protein. To analyse the functions of these proteins, we have studied knockout mice lacking either synapsin I, synapsin II, or both. Mice lacking synapsins are viable and fertile with no gross anatomical abnormalities, but experience seizures with a frequency proportional to the number of mutant alleles. Synapsin-II and double knockouts, but not synapsin-I knockouts, exhibit decreased post-tetanic potentiation and severe synaptic depression upon repetitive stimulation. Intrinsic synaptic-vesicle membrane proteins, but not peripheral membrane proteins or other synaptic proteins, are slightly decreased in individual knockouts and more severely reduced in double knockouts, as is the number of synaptic vesicles. Thus synapsins are not required for neurite outgrowth, synaptogenesis or the basic mechanics of synaptic vesicle traffic, but are essential for accelerating this traffic during repetitive stimulation. The phenotype of the synapsin knockouts could be explained either by deficient recruitment of synaptic vesicles to the active zone, or by impaired maturation of vesicles at the active zone, both of which could lead to a secondary destabilization of synaptic vesicles.

Synapsin I, the major phosphoprotein of synaptic vesicles, is thought to play a central role in neurotransmitter release. Here we introduce a null mutation into the murine synapsin I gene by homologous recombination. Mice with no detectable synapsin I manifest no apparent changes in well-being or gross nervous system function. Thus, synapsin I is not essential for neurotransmitter release. Electrophysiology reveals that mice lacking synapsin I exhibit a selective increase in paired pulse facilitation, with no major alterations in other synaptic parameters such as long-term potentiation. In addition to potential redundant functions shared with other proteins, synapsin I in normal mice may function to limit increases in neurotransmitter release elicited by residual Ca2+ after an initial stimulus.

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