IMPAIRMENT OF SYNAPTIC VESICLE CLUSTERING AND OF SYNAPTIC TRANSMISSION, AND INCREASED SEIZURE PROPENSITY, IN SYNAPSIN I-DEFICIENT MICE

Synapsin I has been proposed to be involved in the modulation of neurotransmitter release by controlling the availability of synaptic vesicles for exofytosis. To further understand the role of synapsin I in the function of adult nerve terminals, we studied synapsin I-deficient mice generated by homologous recombination, The organization of synaptic vesicles at presynaptic terminals of synapsin I-deficient mice was markedly altered: densely packed vesicles were only present in a narrow rim at active zones, whereas the majority of vesicles were dispersed throughout the terminal area, This was in contrast to the organized;vesicle clusters present in terminals of wild-type animals, Release of glutamate from nerve endings, induced by K+, 4-aminopyridine, or a Ca2+ ionophore, was markedly decreased in synapsin I mutant mice, The recovery of synaptic transmission after depletion of neurotransmitter by high-frequency stimulation was greatly delayed, Finally, synapsin I-deficient mice exhibited a strikingly increased response to electrical stimulation, as measured by electrographic acid behavioral seizures, These results provide strong support for the hypothesis that synapsin I plays a key role in the regulation of nerve terminal function in mature synapses.