Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Postsynaptic GABAB Receptor Activity Regulates Excitatory Neuronal Architecture and Spatial Memory.
M. Terunuma, R. Revilla-Sanchez, I. M. Quadros, Q. Deng, T. Z. Deeb, M. Lumb, P. Sicinski, P. G. Haydon, M. N. Pangalos, and S. J. Moss (2014)
J. Neurosci. 34, 804-816
   Abstract »    Full Text »    PDF »
The Ability of BDNF to Modify Neurogenesis and Depressive-Like Behaviors Is Dependent upon Phosphorylation of Tyrosine Residues 365/367 in the GABAA-Receptor {gamma}2 Subunit.
M. Vithlani, R. M. Hines, P. Zhong, M. Terunuma, D. J. Hines, R. Revilla-Sanchez, R. Jurd, P. Haydon, M. Rios, N. Brandon, et al. (2013)
J. Neurosci. 33, 15567-15577
   Abstract »    Full Text »    PDF »
Tyrosine Phosphorylation of GABAA Receptor {gamma}2-Subunit Regulates Tonic and Phasic Inhibition in the Thalamus.
F. Nani, D. P. Bright, R. Revilla-Sanchez, V. Tretter, S. J. Moss, and T. G. Smart (2013)
J. Neurosci. 33, 12718-12727
   Abstract »    Full Text »    PDF »
Enhanced Tonic Inhibition Influences the Hypnotic and Amnestic Actions of the Intravenous Anesthetics Etomidate and Propofol.
K. Kretschmannova, R. M. Hines, R. Revilla-Sanchez, M. Terunuma, V. Tretter, R. Jurd, M. B. Kelz, S. J. Moss, and P. A. Davies (2013)
J. Neurosci. 33, 7264-7273
   Abstract »    Full Text »    PDF »
Gravin Orchestrates Protein Kinase A and {beta}2-Adrenergic Receptor Signaling Critical for Synaptic Plasticity and Memory.
R. Havekes, D. A. Canton, A. J. Park, T. Huang, T. Nie, J. P. Day, L. A. Guercio, Q. Grimes, V. Luczak, I. H. Gelman, et al. (2012)
J. Neurosci. 32, 18137-18149
   Abstract »    Full Text »    PDF »
GABAergic Inhibition of Histaminergic Neurons Regulates Active Waking But Not the Sleep-Wake Switch or Propofol-Induced Loss of Consciousness.
A. Y. Zecharia, X. Yu, T. Gotz, Z. Ye, D. R. Carr, P. Wulff, B. Bettler, A. L. Vyssotski, S. G. Brickley, N. P. Franks, et al. (2012)
J. Neurosci. 32, 13062-13075
   Abstract »    Full Text »    PDF »
Stabilization of GABAA Receptors at Endocytic Zones Is Mediated by an AP2 Binding Motif within the GABAA Receptor {beta}3 Subunit.
K. R. Smith, J. Muir, Y. Rao, M. Browarski, M. C. Gruenig, D. F. Sheehan, V. Haucke, and J. T. Kittler (2012)
J. Neurosci. 32, 2485-2498
   Abstract »    Full Text »    PDF »
The Dynamic Modulation of GABAA Receptor Trafficking and Its Role in Regulating the Plasticity of Inhibitory Synapses.
M. Vithlani, M. Terunuma, and S. J. Moss (2011)
Physiol Rev 91, 1009-1022
   Abstract »    Full Text »    PDF »
NMDA receptors regulate GABAA receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the {gamma}2 subunit.
J. Muir, I. L. Arancibia-Carcamo, A. F. MacAskill, K. R. Smith, L. D. Griffin, and J. T. Kittler (2010)
PNAS 107, 16679-16684
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882