Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses

Abstract

Synapses mediate information flow between neurons and undergo plastic changes in response to experience, which is critical for learning and memory. Conversely, synaptic defects impair information processing and underlie many brain pathologies. Rho-family GTPases control synaptogenesis by transducing signals from extracellular stimuli to the cytoskeleton and nucleus. The Rho-GTPases Rac1 and Cdc42 promote synapse development and the growth of axons and dendrites, while RhoA antagonizes these processes. Despite its importance, many aspects of Rho-GTPase signaling remain relatively unknown. Rho-GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). Though the number of both GEFs and GAPs greatly exceeds that of Rho-GTPases, loss of even a single GEF or GAP often has profound effects on cognition and behavior. Here, we explore how the actions of specific GEFs and GAPs give rise to the precise spatiotemporal activation patterns of Rho-GTPases in neurons. We consider the effects of coupling GEFs and GAPs targeting the same Rho-GTPase and the modular pathways that connect specific cellular stimuli with a given Rho-GTPase via different GEFs. We discuss how the creation of sharp borders between Rho-GTPase activation zones is achieved by pairing a GEF for one Rho-GTPase with a GAP for another and the extensive crosstalk between different Rho-GTPases. Given the importance of synapses for cognition and the fundamental roles that Rho-GTPases play in regulating them, a detailed understanding of Rho-GTPase signaling is essential to the progress of neuroscience.

Introduction

The human brain contains approximately 100 billion neurons that communicate via specialized sites of contact called synapses [1]. Most excitatory synapses in the brain are situated on dendritic spines, small actin-rich protrusions on dendrites [2]. Spines undergo rapid changes in shape and number in response to stimuli [3]. This remodeling is critical for synapse formation and refinement and for the synaptic plasticity that underlies learning and memory [4]. Abnormal spine morphogenesis results in impaired information processing and is linked to numerous neurodevelopmental, neuropsychiatric, and neurodegenerative disorders [5]. Thus, uncovering the mechanisms regulating the formation and plasticity of spines and synapses will provide critical insights into brain function and the treatment of brain disorders.

Rho-family GTPases direct the actin dynamics that drive the formation and remodeling of spines and synapses [6]. Typically, the Rho-GTPases Rac1 and Cdc42 promote the formation, growth, and maintenance of spines, whereas RhoA inhibits these processes [6]. Rho-GTPases cycle between an active GTP-bound state and an inactive GDP-bound state. When active, they interact with specific effectors and initiate signaling pathways that control cytoskeletal dynamics, membrane trafficking, and gene expression [7]. To coordinate these processes properly, Rho GTPases must be regulated with great spatiotemporal precision [8]. Two classes of proteins control the on/off cycling of Rho GTPases. Guanine nucleotide exchange factors (GEFs) activate Rho GTPases by catalyzing GDP/GTP exchange, whereas GTPase-activating proteins (GAPs) inhibit Rho GTPases by stimulating GTP hydrolysis [9]. Guanine dissociation inhibitors (GDIs) also negatively regulate Rho GTPases by sequestering inactive Rho GTPases in the cytosol [10].

Considerable evidence links aberrant Rho-GTPase signaling to brain disorders associated with spine and synapse defects [5]. For instance, mutations in genes encoding Rho-GTPase regulators and effectors cause intellectual disabilities in humans [11]. Furthermore, altered Rac1 signaling is implicated in the pathogenesis of Fragile X syndrome [12], [13], Rett syndrome [14], schizophrenia [15], and substance abuse [16]. Rac1 is also downregulated in patients with major depressive disorder and in mice subjected to chronic social defeat, resulting in depression-related behaviors and abnormal spine remodeling [17]. Dysregulated RhoA signaling is likewise implicated in neurodevelopmental disorders associated with autism [18], [19]. Although precise spatiotemporal regulation of Rho-GTPase signaling is necessary for formation and maintenance of functional synapses, little is known about how this is achieved. Multiple GEFs and GAPs exist for each Rho-GTPase [9], but it is unclear how these regulatory proteins sculpt Rho-GTPase activities in space and time, specify cellular responses, and regulate crosstalk between Rho-GTPase family members. Here, we will discuss recent data that are shedding new light on how Rho-GTPase signaling is precisely regulated in cells, with emphasis on pathways essential to the formation and plasticity of excitatory synapses.