Journal article
Deficits in spatial memory correlate with modified γ-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus
Proceedings of the National Academy of Sciences - PNAS, Vol.106(47), pp.20039-20044
11/24/2009
DOI: 10.1073/pnas.0908840106
PMCID: PMC2785288
PMID: 19903874
Abstract
Fast synaptic inhibition in the brain is largely mediated by γ-aminobutyric acid receptors (GABA
A
R). While the pharmacological manipulation of GABA
A
R 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 GABA
A
Rs γ2 subunit, a posttranslational modification that is critical for their functional modulation, has been ablated. These animals exhibited enhanced GABA
A
R 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 GABA
A
R function involving just two tyrosine residues in the γ2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.
Details
- Title: Subtitle
- Deficits in spatial memory correlate with modified γ-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus
- Creators
- Verena Tretter - Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United KingdomRaquel Revilla-Sanchez - Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111Catriona Houston - Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United KingdomMiho Terunuma - Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111Robbert Havekes - Department of Biology, University of Pennsylvania, Philadelphia, PA 19104Cédrick Florian - Department of Biology, University of Pennsylvania, Philadelphia, PA 19104Rachel Jurd - Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111Mansi Vithlani - Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United KingdomGuido Michels - Department of Internal Medicine III University of Cologne, 50937 Cologne, GermanyAndrés Couve - Programa de Fisiología y Biofísica, Universidad de Chile, Independencia 1027, Santiago, ChileWerner Sieghart - Centre for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria; andNicholas Brandon - Neuroscience Discovery, Wyeth Research, Princeton, NJ 08852Ted Abel - Department of Biology, University of Pennsylvania, Philadelphia, PA 19104Trevor G Smart - Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United KingdomStephen J Moss - Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United Kingdom
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.106(47), pp.20039-20044
- DOI
- 10.1073/pnas.0908840106
- PMID
- 19903874
- PMCID
- PMC2785288
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 11/24/2009
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065834902771
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