期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13209-13214
DOI：10.1073/pnas.1616206113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceLearning and memory are caused by changes in strength of communication between neurons at synapses. Both brief changes (short-term plasticity) and long-lasting changes (long-term plasticity) are important. Synaptic transmission is initiated by calcium channels, which are regulated by calcium-sensor proteins that induce short-term synaptic plasticity. We studied genetically modified mice with a mutation in the binding site for calcium-sensor proteins on calcium channels, which alters short-term synaptic plasticity. Surprisingly, we found that synapses in the hippocampus of these mice also have impaired long-term potentiation. In addition, these mutant mice have impaired spatial learning and memory. Our results show that disruption of calcium-channel regulation by calcium-sensor proteins alters both short-term and long-term plasticity, and these changes impair spatial learning and memory. Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca2+ type 2.1 (CaV2.1) channels. However, the contribution of regulation of CaV2.1 channels to other forms of neuroplasticity and to learning and memory are not known. Here we have studied mice with a mutation (IM-AA) that disrupts regulation of CaV2.1 channels by calmodulin and related calcium sensor proteins. Surprisingly, we find that long-term potentiation (LTP) of synaptic transmission at the Schaffer collateral-CA1 synapse in the hippocampus is substantially weakened, even though this form of synaptic plasticity is thought to be primarily generated postsynaptically. LTP in response to {theta}-burst stimulation and to 100-Hz tetanic stimulation is much reduced. However, a normal level of LTP can be generated by repetitive 100-Hz stimulation or by depolarization of the postsynaptic cell to prevent block of NMDA-specific glutamate receptors by Mg2+. The ratio of postsynaptic responses of NMDA-specific glutamate receptors to those of AMPA-specific glutamate receptors is decreased, but the postsynaptic current from activation of NMDA-specific glutamate receptors is progressively increased during trains of stimuli and exceeds WT by the end of 1-s trains. Strikingly, these impairments in long-term synaptic plasticity and the previously documented impairments in short-term synaptic plasticity in IM-AA mice are associated with pronounced deficits in spatial learning and memory in context-dependent fear conditioning and in the Barnes circular maze. Thus, regulation of CaV2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.
