Impaired spine formation and learning in GPCR kinase 2 interacting protein-1 (GIT1) knockout mice.
The G-protein coupled receptor (GPCR)-kinase interacting proteins 1 and 2 (GIT1 and GIT2) are scaffold proteins with ADP-ribosylating factor GTPase activity. GIT1 and GIT2 control numerous cellular functions and are highly expressed in neurons, endothelial cells and vascular smooth muscle cells. GIT1 promotes dendritic spine formation, growth and motility in cultured neurons, but its role in brain in vivo is unknown. By using global GIT1 knockout mice (GIT1 KO), we show that compared to WT controls, deletion of GIT1 results in markedly reduced dendritic length and spine density in the hippocampus by 36.7% (p<0.0106) and 35.1% (p<0.0028), respectively. This correlated with their poor adaptation to new environments as shown by impaired performance on tasks dependent on learning. We also studied the effect of GIT1 gene deletion on brain microcirculation. In contrast to findings in systemic circulation, GIT1 KO mice had an intact blood-brain barrier and normal regional cerebral blood flow as determined with radiotracers. Thus, our data suggest that GIT1 plays an important role in brain in vivo by regulating spine density involved in synaptic plasticity that is required for processes involved in learning.
Menon
Prashanthi
P
Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Deane
Rashid
R
Sagare
Abhay
A
Lane
Steven M
SM
Zarcone
Troy J
TJ
O'Dell
Michael R
MR
Yan
Chen
C
Zlokovic
Berislav V
BV
Berk
Bradford C
BC
D000223:Adaptation, Psychological / Q000502:physiology; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D048429:Cell Size; D002560:Cerebrovascular Circulation / Q000502:physiology; D049229:Dendritic Spines / Q000502:physiology*; D004777:Environment; D005260:Female; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000098:blood supply / Q000166:cytology / Q000502:physiology; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009483:Neuropsychological Tests
D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; C120766:Git1 protein, mouse