The Chemokine CCL2 Promotes Excitatory Synaptic Transmission in Hippocampal Neurons via GluA1 Subunit Trafficking
En Ji1,2,3 · Yuanyuan Zhang3 · Zhiqiang Li3 · Lai Wei3 · Zhaofa Wu3,4 · Yulong Li3 · Xiang Yu3 · Tian‑Jia Song3,51 Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, and IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
4 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
5 Shandong Provincial Key Medical and Health Laboratory of Psychiatric Genetics of Shandong Mental Health Center, Shandong University, Jinan 250014, China
Abstract
The CC chemokine ligand 2 (CCL2, also known as MCP-1) and its cognate receptor CCR2 have well-characterized roles in chemotaxis. CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability. However, the detailed molecular mechanism underlying this process remains largely unclear. In cultured hippocampal neurons, CCL2 application rapidly upregulated surface expression of GluA1, in a CCR2-dependent manner, assayed using SEP-GluA1 live imaging, surface GluA1 antibody staining, and electrophysiology. Using pharmacology and reporter assays, we further showed that CCL2 upregulated surface GluA1 expression primarily via Gαq- and CaMKII-dependent signaling. Consistently, using i.p. injection of lipopolysaccharide to induce neuroinflammation, we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus, an effect blocked in Ccr2−/− mice. Together, these results provide a mechanism through which CCL2, and other secreted molecules that signal through G-protein coupled receptors, can directly regulate synaptic transmission.
Keywords
Synaptic transmission; CCL2; MCP-1; CCR2; CaMKII; AMPA receptor; GluA1
