Araki Yoichi, Zeng Menglong, Zhang Mingjie, Huganir Richard L
Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Neuron. 2015 Jan 7;85(1):173-189. doi: 10.1016/j.neuron.2014.12.023.
SynGAP is a Ras-GTPase activating protein highly enriched at excitatory synapses in the brain. Previous studies have shown that CaMKII and the RAS-ERK pathway are critical for several forms of synaptic plasticity including LTP. NMDA receptor-dependent calcium influx has been shown to regulate the RAS-ERK pathway and downstream events that result in AMPA receptor synaptic accumulation, spine enlargement, and synaptic strengthening during LTP. However, the cellular mechanisms whereby calcium influx and CaMKII control Ras activity remain elusive. Using live-imaging techniques, we have found that SynGAP is rapidly dispersed from spines upon LTP induction in hippocampal neurons, and this dispersion depends on phosphorylation of SynGAP by CaMKII. Moreover, the degree of acute dispersion predicts the maintenance of spine enlargement. Thus, the synaptic dispersion of SynGAP by CaMKII phosphorylation during LTP represents a key signaling component that transduces CaMKII activity to small G protein-mediated spine enlargement, AMPA receptor synaptic incorporation, and synaptic potentiation.
SynGAP是一种在大脑兴奋性突触中高度富集的Ras-GTPase激活蛋白。先前的研究表明，CaMKII和RAS-ERK通路对于包括长时程增强（LTP）在内的几种形式的突触可塑性至关重要。已证明NMDA受体依赖性钙内流可调节RAS-ERK通路及下游事件，这些事件导致LTP期间AMPA受体在突触处积累、棘突增大和突触增强。然而，钙内流和CaMKII控制Ras活性的细胞机制仍不清楚。利用实时成像技术，我们发现海马神经元在诱导LTP时，SynGAP会迅速从棘突中分散，且这种分散依赖于CaMKII对SynGAP的磷酸化。此外，急性分散的程度可预测棘突增大的维持情况。因此，LTP期间CaMKII磷酸化导致的SynGAP突触分散代表了一个关键的信号成分，它将CaMKII活性转化为小G蛋白介导的棘突增大、AMPA受体突触整合和突触增强。
