Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins.
Rho family small GTPases are important regulators of neuronal development. Defective Rho regulation causes nervous system dysfunctions including mental retardation and Alzheimer's disease. Rac1, a member of the Rho family, regulates dendritic spines and excitatory synapses, but relatively little is known about how synaptic Rac1 is negatively regulated. Breakpoint cluster region (BCR) is a Rac GTPase-activating protein known to form a fusion protein with the c-Abl tyrosine kinase in Philadelphia chromosome-positive chronic myelogenous leukemia. Despite the fact that BCR mRNAs are abundantly expressed in the brain, the neural functions of BCR protein have remained obscure. We report here that BCR and its close relative active BCR-related (ABR) localize at excitatory synapses and directly interact with PSD-95, an abundant postsynaptic scaffolding protein. Mice deficient for BCR or ABR show enhanced basal Rac1 activity but only a small increase in spine density. Importantly, mice lacking BCR or ABR exhibit a marked decrease in the maintenance, but not induction, of long-term potentiation, and show impaired spatial and object recognition memory. These results suggest that BCR and ABR have novel roles in the regulation of synaptic Rac1 signaling, synaptic plasticity, and learning and memory, and that excessive Rac1 activity negatively affects synaptic and cognitive functions.
Oh
Daeyoung
D
National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Han
Seungnam
S
Seo
Jinsoo
J
Lee
Jae-Ran
JR
Choi
Jeonghoon
J
Groffen
John
J
Kim
Karam
K
Cho
Yi Sul
YS
Choi
Han-Saem
HS
Shin
Hyewon
H
Woo
Jooyeon
J
Won
Hyejung
H
Park
Soon Kwon
SK
Kim
Soo-Young
SY
Jo
Jihoon
J
Whitcomb
Daniel J
DJ
Cho
Kwangwook
K
Kim
Hyun
H
Bae
Yong Chul
YC
Heisterkamp
Nora
N
Choi
Se-Young
SY
Kim
Eunjoon
E
D000818:Animals; D019470:Biolistics; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D004594:Electrophysiology; D020690:GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis* / Q000235:genetics
C553409:Abr protein, rat; D020690:GTPase-Activating Proteins; C534771:Bcr protein, rat; D017346:Protein Serine-Threonine Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein