Impaired GABAA receptor endocytosis and its correlation to spatial memory deficits

Abstract

GABA_A receptors mediate the majority of fast synaptic inhibition in the mammalian brain. Mechanisms that regulate GABA_A function are thus of critical importance in modulating overall synaptic inhibition. Phosphorylation of GABA_A receptor subunits is one such mechanism that leads to the dynamic modulation of GABA_A receptor function. In particular, phosphorylation of tyrosine residues 365 and 367 (Y365, Y367) within the γ2 subunit of GABAA receptors has been shown in previous in vitro studies to negatively regulate clathrin-dependent endocytosis of GABA_A receptors and to enhance the efficacy of synaptic inhibition. With the aim of investigating the impact of this phosphorylation-dependent modulation of GABA_A receptors on animal behavior, we recently developed a knock-in mouse in which these critical tyrosine residues within the γ2 subunit have been mutated to phenylalanines (Y365/7F). These animals exhibited enhanced GABA_A receptor accumulation at postsynaptic inhibitory synaptic specializations on pyramidal neurons within the hippocampus, primarily due to aberrant trafficking within the endocytic pathway. We found that this enhanced inhibition correlated with a specific deficit in spatial memory in these mice, without modifying a number of other behavioral paradigms. Here, we summarize our recently reported observations and further discuss their possible implications.

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Acknowledgements

S.J.M. is supported by National Institute of Neurological Disorders and Stroke Grants (NS047478, NS051195, NS056359, NS054900), the Medical Research Council, and the Wellcome Trust. R.J. is supported by the Maltz Family Foundation as a National Alliance for Research on Schizophrenia and Depression Young Investigator.

Figures and Tables

Figure 1 Model summarizing the regulation of GABA_A receptor endocytosis by the Yxxφ motif within the GABA_A receptor γ2 subunit. (A) Endocytosis via clathrin-coated vesicles (CCV) is the major internalization mechanism for neuronal GABA_A receptors (GABA_ARs). The intracellular domain of the γ2 subunit of the GABA_AR interacts with the μ2 subunit of the clathrin-adaptor protein 2 (AP2). This binding is mediated via a Yxxφ motif contained within the γ2 subunit that is centered around tyrosine residues 365 and 367. (B) Binding of the AP2 complex is negatively regulated by mutation of these tyrosine residues to phenylalanines. γ2(Y365/7F) heterozygous mutant mice have decreased levels of receptor endocytosis and increased cell-surface levels of γ2-containing GABA_ARs. We have also demonstrated that these mutant mice display an enhanced efficacy of inhibitory synaptic transmission in the CA3 region of the hippocampus.12

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