GSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons

• Published in: Nature communications 2016-03, Vol.7 (1), p.10873-10873, Article 10873
• Main Authors: Gu, Xinglong, Mao, Xia, Lussier, Marc P., Hutchison, Mary Anne, Zhou, Liang, Hamra, F. Kent, Roche, Katherine W., Lu, Wei
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 14/19; 42/109; 631/378/1595/1554; 631/378/548; 631/45/612/1237; 631/80/86; 82/29; 82/80; 9/74; 96; 96/34; 96/35; Animals; Claudins - genetics; Claudins - metabolism; Gene Deletion; HEK293 Cells; Hippocampus - cytology; Humanities and Social Sciences; Humans; multidisciplinary; Mutation; Neurons - physiology; Plasmids; Protein Subunits; Rats; Real-Time Polymerase Chain Reaction; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); Synapses - physiology; Synaptic Transmission - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10873

Regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is a key mechanism for synaptic plasticity. In the brain, AMPARs assemble with a number of auxiliary subunits, including TARPs, CNIHs and CKAMP44, which are important for AMPAR forward trafficking to synapses. Here we report that the membrane protein GSG1L negatively regulates AMPAR-mediated synaptic transmission. Overexpression of GSG1L strongly suppresses, and GSG1L knockout (KO) enhances, AMPAR-mediated synaptic transmission. GSG1L-dependent regulation of AMPAR synaptic transmission relies on the first extracellular loop domain and its carboxyl-terminus. GSG1L also speeds up AMPAR deactivation and desensitization in hippocampal CA1 neurons, in contrast to the effects of TARPs and CNIHs. Furthermore, GSG1L association with AMPARs inhibits CNIH2-induced slowing of the receptors in heterologous cells. Finally, GSG1L KO rats have deficits in LTP and show behavioural abnormalities in object recognition tests. These data demonstrate that GSG1L represents a new class of auxiliary subunit with distinct functional properties for AMPARs. The molecular mechanism controlling the trafficking and function of AMPARs at synapses are not fully understood. Here the authors show that GSG1L, a membrane protein, negatively regulates AMPAR-mediated synaptic transmission and represents a new class of AMPAR auxiliary subunit.