Nanou Evanthia, Scheuer Todd, Catterall William A
Department of Pharmacology, University of Washington, Seattle, WA 98195-7280.
Department of Pharmacology, University of Washington, Seattle, WA 98195-7280
Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13209-13214. doi: 10.1073/pnas.1616206113. Epub 2016 Oct 31.
Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca type 2.1 (Ca2.1) channels. However, the contribution of regulation of Ca2.1 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 Ca2.1 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 θ-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 Mg 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 Ca2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.
许多形式的短期突触可塑性依赖于对突触前电压门控钙2.1型（Ca2.1）通道的调节。然而，Ca2.1通道调节对其他形式的神经可塑性以及学习和记忆的贡献尚不清楚。在这里，我们研究了一种具有突变（IM-AA）的小鼠，该突变破坏了钙调蛋白和相关钙传感器蛋白对Ca2.1通道的调节。令人惊讶的是，我们发现海马体中Schaffer侧支-CA1突触处突触传递的长时程增强（LTP）显著减弱，尽管这种形式的突触可塑性被认为主要是在突触后产生的。对θ波爆发刺激和100Hz强直刺激的LTP大大降低。然而，通过重复100Hz刺激或使突触后细胞去极化以防止Mg对NMDA特异性谷氨酸受体的阻断，可以产生正常水平的LTP。NMDA特异性谷氨酸受体的突触后反应与AMPA特异性谷氨酸受体的突触后反应之比降低，但在一系列刺激过程中，NMDA特异性谷氨酸受体激活产生的突触后电流逐渐增加，在1秒刺激结束时超过野生型。引人注目的是，IM-AA小鼠在长期突触可塑性方面的这些损伤以及先前记录的短期突触可塑性损伤与情境依赖性恐惧条件反射和巴恩斯圆形迷宫中空间学习和记忆的明显缺陷有关。因此，钙传感器蛋白对Ca2.1通道的调节是小鼠正常短期突触可塑性、LTP以及空间学习和记忆所必需的。
