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 exocytosis. 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 and 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.
Li
L
L
Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021, USA.
Chin
L S
LS
Shupliakov
O
O
Brodin
L
L
Sihra
T S
TS
Hvalby
O
O
Jensen
V
V
Zheng
D
D
McNamara
J O
JO
Greengard
P
P
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D004558:Electric Stimulation; D004569:Electroencephalography; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008854:Microscopy, Electron; D017470:Receptors, Glutamate / Q000378:metabolism; D012016:Reference Values; D012640:Seizures / Q000235:genetics / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology; D016704:Synapsins / Q000172:deficiency* / Q000235:genetics; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000502:physiology* / Q000648:ultrastructure*; D013574:Synaptosomes / Q000502:physiology* / Q000648:ultrastructure
D017470:Receptors, Glutamate; D016704:Synapsins; D018698:Glutamic Acid