Regulation of Synaptic Rac1 Activity, Long-Term Potentiation Maintenance, and Learning and Memory by BCR and ABR Rac GTPase-Activating Proteins

Abstract

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.

Src Homology 2 Domain Containing Protein 5 (SH2D5) Binds the Breakpoint Cluster Region Protein, BCR, and Regulates Levels of Rac1-GTP

“…We found that BCR expression decreases through development (Fig. 5, B and C), which is supported by Oh et al (9), who observed decreased levels of BCR expression as mice age. It is tempting to speculate that this differential expression may be due to mutual regulation, although this remains to be investigated.…”

“…Because of the shared domain architecture of SH2D5 with Tyr(P) recognition adaptor proteins, we reasoned that a first step in unraveling the function of SH2D5 would be to analyze its interaction profiles in unstimulated cells and cells in which tyrosine phosphorylation is induced by exposure to pervanadate. Here, we characterize a novel interaction of the SH2D5 PTB domain with breakpoint cluster region protein (BCR), a regulator of Rho GTPases (9,10). We show enrichment of SH2D5 and BCR proteins in neuronal cell types.…”

When Is the Hippocampus Involved in Recognition Memory?

“…Some papers have reported that manipulations of the hippocampus impair novel object preference tasks (Mansuy et al, 1998;Pittenger et al, 2002;Oh et al, 2010). However, in a number of these studies such variation may be accounted for by differences in the experimental paradigms used, in particular the type or number of stimuli presented in the sample phase.…”

The small GTPase RhoA, but not Rac1, is essential for conditioned aversive memory formation through regulation of actin rearrangements in rat dorsal hippocampus

“…RhoA, Rac and Cdc42 are the three best-studied Rho GTPases, which control the formation of distinct F-actin-based structures [39,40] . Studies have shown that RhoA and Rac1 are important for structural aspects of the mature neuron [41] and are related to learning and memory [42,43] . The present study set about to explore the relationship between the small Rho GTPases and drug withdrawal-induced hippocampal actin polymerization.…”