Rho Signaling in Synaptic Plasticity, Memory, and Brain Disorders

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.

Keywords: Rho GTPases; brain disorders; dendritic spine; long-term depression; long-term potentiation.

FIGURE 1

Role of Rho GTPases in modulating dendritic spine density and morphology. The activation of Rac1 and Cdc42 leads to increased immature spines, some of which will undergo morphological changes to obtain mature morphology through Rac1-dependent mechanisms, whereas others will be eliminated by RhoA-dependent processes.

FIGURE 2

Rho GTPases in AMPAR expression, LTP and LTD. RhoA, Cdc42, and Rac1 can participate in the regulation of the synaptic insertion, internalization and membrane stability of AMPARs during LTP and LTD. These GPTases are activated by NMDARs or other surface proteins through various GAPs and GEFs.

FIGURE 3

Rho GTPase signaling pathways in actin dynamics and synaptic function. Rac1, Cdc42, and RhoA regulate actin dynamics either through cofilin or Arp2/3 complex pathways. Rac1/Cdc42 and RhoA activate PAKs and ROCKs, respectively, which phosphorylate and activate cofilin kinase LIMKs and inhibit cofilin phosphatase SSH, both leading to inactivation of cofilin thus reduced actin disassembly. Rac1 and Cdc42 promote actin assembly through the Arp2/3 complex and the formin-related protein (Dia) via WAVE and WASP, respectively.