期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 47, 页码 20039-20044出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0908840106
关键词
cognition; GABA(A) receptor; inhibitory synapses
资金
- National Institute of Neurological Disorders and Stroke [NS047478, NS048045, NS051195, NS056359, NS054900]
- Medical Research Council
- Wellcome Trust
- European Union Marie Curie fellowship
- American Heart Association
- Netherlands Organization for Scientific Research Rubicon
- National Alliance for Research on Schizophrenia and Depression Young Investigator Award
- National Institute of Mental Health [P50MH064045]
- Tufts Center for Neuroscience Research [P30 NS047243]
- Medical Research Council [G0601529] Funding Source: researchfish
- MRC [G0601529] Funding Source: UKRI
Fast synaptic inhibition in the brain is largely mediated by gamma-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 gamma 2 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 gamma 2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.
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