Rho Signaling in Synaptic Plasticity, Memory, and Brain Disorders.

Youssif Ben Zablah,Haorui Zhang,Haiwang Zhang,Zhengping Jia

doi:10.3389/fcell.2021.729076

Abstract

Memory impairments are associated with many brain disorders such as autism, Alzheimer’s disease, and depression. Forming memories involves modifications of synaptic transmission and spine morphology. The Rho family small GTPases are key regulators of synaptic plasticity by affecting various downstream molecules to remodel the actin cytoskeleton. In this paper, we will review recent studies on the roles of Rho proteins in the regulation of hippocampal long-term potentiation (LTP) and long-term depression (LTD), the most extensively studied forms of synaptic plasticity widely regarded as cellular mechanisms for learning and memory. We will also discuss the involvement of Rho signaling in spine morphology, the structural basis of synaptic plasticity and memory formation. Finally, we will review the association between brain disorders and abnormalities of Rho function. It is expected that studying Rho signaling at the synapse will contribute to the understanding of how memory is formed and disrupted in diseases.

Highlights

The synapse is a highly specialized structure connecting two cells and it serves as the main site where neurons communicate and transmit signals between each other
Synaptic structure was firstly described by Gray (1959), and it consists of vesicle-bearing presynaptic terminals that originate from axons and the post-synaptic component found on the cell body, dendrites or a dendritic spines
Increased Rac1 activity by knocking out/down Rac1 GTPase-activating proteins (GAPs) proteins or overexpressing Rac1 had no effects on LFSinduced longterm depression (LTD) (Oh et al, 2010; Benoist et al, 2013; Valdez et al, 2016), in KO mice lacking kinesin family member 21B (Kif21B), a microtubule-dependent molecular motor that regulates the engulfment of the Rac1-guanine nucleotide-exchange factors (GEFs), ELMO1/DOCK complex and enhances Rac1 activity, was found to have unstable low-frequency stimulation (LFS)-induced LTD without alterations in high-frequency stimulation (HFS)-induced long-term potentiation (LTP) at CA1 synapses (Morikawa et al, 2018)

Summary

INTRODUCTION

The synapse is a highly specialized structure connecting two cells and it serves as the main site where neurons communicate and transmit signals between each other. In contrast to the effects of Rac and Cdc, the expression of constitutively active RhoA in hippocampal neurons or slice cultures consistently resulted in simplified dendritic trees and reduced spine density (Nakayama et al, 2000; Tashiro et al, 2000; Impey et al, 2010). It is important to note that the increased spines caused by RhoA inhibition or Rac activation appeared to be immature spines with filopodia-like or lamellipodia-like morphology (Nakayama et al, 2000; Tashiro et al, 2000) These results suggest that Rac and Cdc are involved in the induction and maintenance of spines, whereas RhoA plays a role in the elimination or pruning of immature spines. The balance of Rac1/Cdc and RhoA activity may be critical for establishing and maintaining the homeostasis of dendritic spine density in the brain

RHO GTPases IN SPINE FORMATION

RHO GTPases IN SYNAPTIC PLASTICITY

RHO SIGNALING PATHWAYS

RHO GTPases IN MEMORY

RHO GTPases IN BRAIN DISEASES

AUTISM SPECTRUM DISORDER

Fragile X Syndrome

SUMMARY