Huang Yan-You, Zakharenko Stanislav S, Schoch Susanne, Kaeser Pascal S, Janz Roger, Südhof Thomas C, Siegelbaum Steven A, Kandel Eric R
Center for Neurobiology and Behavior, New York State Psychiatric Institute, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9365-70. doi: 10.1073/pnas.0503777102. Epub 2005 Jun 20.
The synaptic vesicle protein Rab3A is a small GTP-binding protein that interacts with rabphilin and RIM1alpha, two presynaptic substrates of protein kinase A (PKA). Mice lacking RIM1alpha and Rab3A have a defect in PKA-dependent and NMDA receptor (NMDAR)-independent presynaptic long-term potentiation (LTP) at hippocampal mossy-fiber and cerebellar parallel-fiber synapses. In contrast, the NMDAR-dependent and PKA-independent early phase of LTP at hippocampal CA3-CA1 synapses does not require these presynaptic proteins. Here, we ask whether Rab3A and RIM1alpha participate in forms of LTP that require both PKA and NMDAR activation. We find that Rab3A is necessary for corticoamygdala LTP and late-phase LTP at CA3-CA1 synapses, two forms of LTP that require NMDAR and PKA activation. The latter form of LTP also requires RIM1alpha. These results provide genetic evidence that presynaptic proteins are required in LTP induced through the postsynaptic activation of NMDARs. Thus Rab3A and its effectors are general modules for four distinct types of PKA-dependent LTP in the brain.
突触小泡蛋白Rab3A是一种小的GTP结合蛋白,它与rabphilin和RIM1α相互作用,这两者是蛋白激酶A(PKA)的两种突触前底物。缺乏RIM1α和Rab3A的小鼠在海马苔藓纤维和小脑平行纤维突触处的PKA依赖性和N-甲基-D-天冬氨酸受体(NMDAR)非依赖性突触前长时程增强(LTP)方面存在缺陷。相比之下,海马CA3-CA1突触处LTP的NMDAR依赖性和PKA非依赖性早期阶段不需要这些突触前蛋白。在此,我们探究Rab3A和RIM1α是否参与需要PKA和NMDAR激活的LTP形式。我们发现Rab3A对于皮质杏仁核LTP以及CA3-CA1突触处的晚期LTP是必需的,这两种LTP形式需要NMDAR和PKA激活。后一种LTP形式也需要RIM1α。这些结果提供了遗传学证据,表明在通过NMDAR的突触后激活诱导的LTP中需要突触前蛋白。因此,Rab3A及其效应器是大脑中四种不同类型的PKA依赖性LTP的通用模块。