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PNAS 106 (47): 20039-20044

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

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

Verena Trettera,1, Raquel Revilla-Sanchezb,1, Catriona Houstona,1, Miho Terunumab,1, Robbert Havekesc,1, Cédrick Florianc,1, Rachel Jurdb,1, Mansi Vithlania,b, Guido Michelsd, Andrés Couvee, Werner Sieghartf, Nicholas Brandong, Ted Abelc, Trevor G. Smarta, and Stephen J. Mossa,b,2

aDepartment of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United Kingdom; bDepartment of Neuroscience, Tufts University School of Medicine, Boston, MA 02111; cDepartment of Biology, University of Pennsylvania, Philadelphia, PA 19104; dDepartment of Internal Medicine III University of Cologne, 50937 Cologne, Germany; ePrograma de Fisiología y Biofísica, Universidad de Chile, Independencia 1027, Santiago, Chile; fCentre for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria; and gNeuroscience Discovery, Wyeth Research, Princeton, NJ 08852

Edited by Richard L. Huganir, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 2, 2009

Received for publication August 6, 2009.

Abstract: Fast synaptic inhibition in the brain is largely mediated by {gamma}-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 {gamma}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 {gamma}2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.

Key Words: cognition • GABAA receptor • inhibitory synapses

Author contributions: V.T., R.R.-S., M.T., R.H., C.F., R.J., M.V., A.C., N.B., T.A., T.G.S., and S.J.M. designed research; V.T., R.R.-S., C.H., M.T., R.H., C.F., R.J., G.M., A.C., N.B., T.A., and S.J.M. performed research; M.V. and W.S. contributed new reagents/analytic tools; V.T., R.R.-S., C.H., M.T., R.H., C.F., R.J., M.V., T.G.S., and S.J.M. analyzed data; and T.A., T.G.S., and S.J.M. wrote the paper.

1V.T., R.R.-S., C.H., M.T., R.H., C.F., and R.J. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0908840106/DCSupplemental.

2To whom correspondence should be addressed. E-mail: stephen.moss{at}tufts.edu

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