Deficits in spatial memory correlate with modified {gamma}-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus.
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.
Tretter
Verena
V
Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United Kingdom.
Revilla-Sanchez
Raquel
R
Houston
Catriona
C
Terunuma
Miho
M
Havekes
Robbert
R
Florian
Cédrick
C
Jurd
Rachel
R
Vithlani
Mansi
M
Michels
Guido
G
Couve
Andrés
A
Sieghart
Werner
W
Brandon
Nicholas
N
Abel
Ted
T
Smart
Trevor G
TG
Moss
Stephen J
SJ
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*
D011963:Receptors, GABA-A; D014443:Tyrosine