Deficits in spatial memory correlate with modified gamma-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus

Tretter, V; Revilla-Sanchez, R; Houston, C; Terunuma, M; Havekes, R; Florian, C; Jurd, R; Vithlani, M; Michels, G; couve, a; Sieghart, W; Brandon, N; Abel, T; Smart, TG; Moss, SJ

Abstract

Fast synaptic inhibition in the brain is largely mediated by ?-aminobutyric acid receptors (GABAAR). While the pharmacological manipulation of GABAAR function by therapeutic agents, such as benzodiazepines can have profound effects on neuronal excitation and behavior, the endogenous mechanisms neurons use to regulate the efficacy of synaptic inhibition and their impact on behavior remains poorly understood. To address this issue, we created a knock-in mouse in which tyrosine phosphorylation of the GABAARs ?2 subunit, a posttranslational modification that is critical for their functional modulation, has been ablated. These animals exhibited enhanced GABAAR accumulation at postsynaptic inhibitory synaptic specializations on pyramidal neurons within the CA3 subdomain of the hippocampus, primarily due to aberrant trafficking within the endocytic pathway. This enhanced inhibition correlated with a specific deficit in spatial object recognition, a behavioral paradigm dependent upon CA3. Thus, phospho-dependent regulation of GABAAR function involving just two tyrosine residues in the ?2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.

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Título según WOS: Deficits in spatial memory correlate with modified gamma-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus
Título según SCOPUS: Deficits in spatial memory correlate with modified ?-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus
Título de la Revista: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volumen: 106
Número: 47
Editorial: United States National Academy of Sciences
Fecha de publicación: 2009
Página de inicio: 20039
Página final: 20044
Idioma: English
URL: http://www.pnas.org/cgi/doi/10.1073/pnas.0908840106
DOI:

10.1073/pnas.0908840106

Notas: ISI, SCOPUS