Abstract
Neurotransmitter release is mediated by the SNARE complex, but the role of its phosphorylation has scarcely been elucidated. Although PKC activators are known to facilitate synaptic transmission, there has been a heated debate on whether PKC mediates facilitation of neurotransmitter release through phosphorylation. One of the SNARE proteins, SNAP-25, is phosphorylated at the residue serine-187 by PKC, but its physiological significance has been unclear. To examine these issues, we analyzed mutant mice lacking the phosphorylation of SNAP-25 serine-187 and found that they exhibited reduced release probability and enhanced presynaptic short-term plasticity, suggesting that not only the release process, but also the dynamics of synaptic vesicles was regulated by the phosphorylation. Furthermore, it has been known that the release probability changes with development, but the precise mechanism has been unclear, and we found that developmental changes in release probability of neurotransmitters were regulated by the phosphorylation. These results indicate that SNAP-25 phosphorylation developmentally facilitates neurotransmitter release but strongly inhibits presynaptic short-term plasticity via modification of the dynamics of synaptic vesicles in presynaptic terminals.
Highlights
Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the neurotransmitter glutamate, which is released from synaptic vesicles in the presynaptic terminal through membrane fusion of the terminal and synaptic vesicles in a Ca2+-dependent manner[1], and the released glutamate binds to postsynaptic glutamate receptors and transmits neural information to postsynaptic cells
These results suggested that the fusion process of synaptic vesicles in basal conditions as well as the dynamics of synaptic vesicles during repetitive synaptic activation was severely impaired in KI mice, which indicated that the basal neurotransmitter release probability was decreased, but the synaptic efficacy during repetitive synaptic activation was increased in KI mice
We found that KI mice exhibited several abnormalities of excitatory synaptic transmission in the CA1 region of acute hippocampal slices, including the decreased basal synaptic transmission, the increased paired-pulse ratio indicative of the reduced probability of neurotransmitter release, the increased Post-tetanic potentiation (PTP) and the enhanced synaptic transmission during 5-Hz repetitive stimulation
Summary
Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the neurotransmitter glutamate, which is released from synaptic vesicles in the presynaptic terminal through membrane fusion of the terminal and synaptic vesicles in a Ca2+-dependent manner[1], and the released glutamate binds to postsynaptic glutamate receptors and transmits neural information to postsynaptic cells. There has been a heated debate whether the PKC-activator phorbol ester mediates enhancement of neurotransmitter release through phosphorylation by PKC or through its direct action on release machinery[13] To examine these issues, we generated knock-in (KI) mice deficient in the phosphorylation by replacing serine-187 of SNAP-25 with alanine[14] and analyzed synaptic transmission and plasticity at hippocampal CA1 synapses. We confirmed that these phenotypes were not caused by a decrease of SNAP-25 expression nor by an epileptic seizure These results indicate that this phosphorylation exerts great influence on synaptic functions in the CNS, and it may regulate higher brain functions such as emotion and prevent excessive activities in the brain such as an epileptic seizure through inhibition of presynaptic plasticity
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