title: Deficits in spatial memory correlate with modified {gamma}-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus.
abstract: 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 gamma2 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 gamma2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United Kingdom.
authors.forename: Verena
authors.initials: V
authors.lastname: Tretter
authors.forename: Raquel
authors.initials: R
authors.lastname: Revilla-Sanchez
authors.forename: Catriona
authors.initials: C
authors.lastname: Houston
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.forename: Robbert
authors.initials: R
authors.lastname: Havekes
authors.forename: Cédrick
authors.initials: C
authors.lastname: Florian
authors.forename: Rachel
authors.initials: R
authors.lastname: Jurd
authors.forename: Mansi
authors.initials: M
authors.lastname: Vithlani
authors.forename: Guido
authors.initials: G
authors.lastname: Michels
authors.forename: Andrés
authors.initials: A
authors.lastname: Couve
authors.forename: Werner
authors.initials: W
authors.lastname: Sieghart
authors.forename: Nicholas
authors.initials: N
authors.lastname: Brandon
authors.forename: Ted
authors.initials: T
authors.lastname: Abel
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000818:Animals; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013037:Spatial Behavior / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D014443:Tyrosine