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

Abstract

Fast synaptic inhibition in the brain is largely mediated by γ-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 γ2 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