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

Xinglong Gu,Liang Zhou,Katherine W Roche,F Kent Hamra,Wei Lu,Mary Anne Hutchison,Xia Mao,Marc P Lussier

doi:10.1038/ncomms10873

Abstract

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.

Highlights

Regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is a key mechanism for synaptic plasticity
Together with the data that showed the lack of changes of NMDA excitatory postsynaptic currents (EPSCs), paired-pulse ratio (PPR) and spine density in neurons overexpressing Germ Cell-Specific Gene 1-Like (GSG1L) (Fig. 1b,d and Supplementary Fig. 3), AMPA EPSC and m/spontaneous EPSC (sEPSC) data indicate that overexpression of GSG1L induced a loss of functional AMPA receptors (AMPARs) at the majority of synapses and a reduced amount of functional AMPARs at the remaining synapses (Fig. 1b,e,f)
In agreement with a previous report[10], we found that expression of a CNIH2 short hairpin RNA construct that effectively knocked down CNIH2, but not a control scramble shRNA construct, in hippocampal CA1 neurons sped up AMPAR deactivation kinetics (Fig. 7e and Supplementary Fig. 9)

Summary

Introduction

Regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is a key mechanism for synaptic plasticity. Gene knockout (KO)/knock-in experiments demonstrate that both g8, the dominant TARP in the hippocampus, and CNIHs are required for AMPAR forward trafficking to the neuronal surface and synapses in hippocampal CA1 pyramidal neurons[10,20,21] Both g8 and CNIH2/3 modulate AMPAR biophysical properties by slowing receptor deactivation and desensitization kinetics[7,10,13,17,22,23,24,25,26,27,28,29]. CKAMP44 has been shown to play an important role in positively regulating AMPAR trafficking to synapses and slowing the receptor deactivation kinetics in hippocampal neurons[15] These studies indicate that a general function for TARPs/CNIHs/ CKAMP44 in the hippocampus is to positively regulate AMPAR abundance at synapses and render slower glutamatergic currents. These findings reveal unique roles of GSG1L in the regulation of AMPAR-mediated synaptic transmission in the brain

Methods

Results

Conclusion