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.
National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Daeyoung
D
Oh
Seungnam
S
Han
Jinsoo
J
Seo
Jae-Ran
JR
Lee
Jeonghoon
J
Choi
John
J
Groffen
Karam
K
Kim
Yi Sul
YS
Cho
Han-Saem
HS
Choi
Hyewon
H
Shin
Jooyeon
J
Woo
Hyejung
H
Won
Soon Kwon
SK
Park
Soo-Young
SY
Kim
Jihoon
J
Jo
Daniel J
DJ
Whitcomb
Kwangwook
K
Cho
Hyun
H
Kim
Yong Chul
YC
Bae
Nora
N
Heisterkamp
Se-Young
SY
Choi
Eunjoon
E
Kim
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