The Role of Rac GTPase in Dendritic Spine Morphogenesis and Memory

Abstract

The ability to form memories in the brain is needed for daily functions, and its impairment is associated with human mental disorders. Evidence indicates that long-term memory (LTM)-related processes such as its consolidation, extinction and forgetting involve changes of synaptic efficacy produced by alterations in neural transmission and morphology. Modulation of the morphology and number of dendritic spines has been proposed to contribute to changes in neuronal transmission mediating such LTM-related processes. Rac GTPase activity is regulated by synaptic activation and it can affect spine morphology by controlling actin-regulatory proteins. Recent evidence shows that changes in Rac GTPase activity affect memory consolidation, extinction, erasure and forgetting and can affect spine morphology in brain areas that mediate these behaviors. Altered Rac GTPase activity is associated with abnormal spine morphology and brain disorders. By affecting Rac GTPase activity we can further understand the roles of spine morphogenesis in memory. Moreover, manipulation of Rac GTPase activity may serve as a therapeutic tool for the treatment of memory-related brain diseases.

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

“…Recent studies in animal models have shown that spine alterations in the prefrontal cortex of male HIV-transgenic rats involve an actin depolymerization pathway regulated by the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1) [ 84 ]. Normally, Rac1 activation leads to phosphorylation and activation of p21-activated kinase 1 (PAK1), which phosphorylates LIM kinase 1 (LIMK1), an inhibitor of the actin severing protein cofilin [ 162 , 163 ]. However, activation of Rac1 and PAK1 is reduced in frontal cortex of HIV-transgenic rats [ 84 ], suggesting an increase of cofilin-mediated actin severing that could drive loss of dendritic spines in this region.…”

Beyond Axon Guidance: Roles of Slit-Robo Signaling in Neocortical Formation

“…srGAP3 interacts with a scaffold protein for actin remodeling, WAVE-1, and inhibits Rac1 activity ( Soderling et al, 2002 ). Because either the inhibition of or activation of Rac1 leads to abnormal spine formation ( Costa et al, 2020 ), precise regulation of Rac1 activity is crucial for normal spine formation. Consistent with this notion, both a reduced interaction between srGAP3 and WAVE-1 and knockout of srGAP3 have been shown to decrease the number of spines ( Soderling et al, 2007 ; Carlson et al, 2011 ).…”

Dendritic Spine Plasticity: Function and Mechanisms

“…Hayashi-Takagi et al ( 2015 ) developed a revolutionary approach that finally allowed tackling this question. They developed a photoactivatable form of the Rho GTPase RAC1, known to regulate spine dynamics through the modulation of actin polymerization (Costa et al, 2020 ), which they called paRAC1. RAC1 normally accumulates in recently formed, nascent spines, and constitutive RAC1 activation leads to spine shrinkage and elimination (Tashiro et al, 2000 ).…”

“…Also, recent genetic studies have shown that many mutations associated with neurodevelopmental disorders involve genes encoding regulators of the spine actin cytoskeleton (Borovac et al, 2018 ), validating the hypothesis that mechanisms regulating the actin cytoskeleton may contribute to spine pathology in neurodevelopmental disorders. For a more complete review of actin and ABPs in spinogenesis, please refer to Costa et al ( 2020 ) in this issue of Frontiers in Synaptic Neuroscience, and Borovac et al ( 2018 ).…”

“…These kinases ultimately activate numerous ABPs including Cofilin and Arp2/3 that play essential roles in actin reorganization. The mechanisms by which ABPs induce actin reorganization upon synaptic potentiation have been abundantly studied in other reviews (Borovac et al, 2018 ; Costa et al, 2020 ).…”