Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses

Abstract

Synaptic connections between neurons are essential for every facet of human cognition and are thus regulated with extreme precision. Rho-family GTPases, molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state, comprise a critical feature of synaptic regulation. Rho-GTPases are exquisitely controlled by an extensive suite of activators (GEFs) and inhibitors (GAPs and GDIs) and interact with many different signalling pathways to fulfill their roles in orchestrating the development, maintenance, and plasticity of excitatory synapses of the central nervous system. Among the mechanisms that control Rho-GTPase activity and signalling are cell surface receptors, GEF/GAP complexes that tightly regulate single Rho-GTPase dynamics, GEF/GAP and GEF/GEF functional complexes that coordinate multiple Rhofamily GTPase activities, effector positive feedback loops, and mutual antagonism of opposing Rho-GTPase pathways. These complex regulatory mechanisms are employed by the cells of the nervous system in almost every step of development, and prominently figure into the processes of synaptic plasticity that underlie learning and memory. Finally, misregulation of Rho-GTPases plays critical roles in responses to neuronal injury, such as traumatic brain injury and neuropathic pain, and in neurodevelopmental and neurodegenerative disorders, including intellectual disability, autism spectrum disorder, schizophrenia, and Alzheimer's Disease. Thus, decoding the mechanisms of Rho-GTPase regulation and function at excitatory synapses has great potential for combatting many of the biggest current challenges in mental health.

LSD Modulates Proteins Involved in Cell Proteostasis, Energy Metabolism and Neuroplasticity in Human Cerebral Organoids

“…Our analysis also implicates LSD in pathways essential for structural and functional neuroplasticity, including cytoskeletal regulation and neurotransmitter release. The remodeling of dendrites requires precise control over actin and microtubule dynamics, typically mediated by Rho GTPases (37,40). Our findings suggest a phase in LSD’s mechanism of action characterized by reduced actin polymerization and stabilization of the existing cytoskeleton, aligning with a transition from the initiation to the maintenance of structural plasticity changes (74).…”

Genome binding properties of Zic transcription factors underlie their changing functions during neuronal maturation

“…A substantial group of Zic-dependent developmentally upregulated genes participate in synaptic function ( Gabrd, Slc17a7, Gprc5b ) and neuronal excitability ( Fgf12, Kcnc4, Kcnn2, Kcnq3, Kcnj9, Dpp10 ), and Zic TFs appear to co-regulate groups of genes that coordinate these processes. For example, the candidate Zic TF target Tiam1 is known to activate Rho-GTPase signal cascades to promote synaptic and dendritic plasticity (98–102). Genes that are upstream regulators of Tiam1 ( Klf13 and Ephrins) and also those involved in Rho-GTPase signaling ( Rasal1 , Fgd5 , Plekhg1 , Arhged3, Net1 ) are also candidate Zic targets (103).…”

Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

“…2). Rho GTPases are critical in synaptic regulation (Duman et al, 2021). In neurons, the Rho GTPase Rac1 promotes the growth of axons and dendrites and of spines/synapses, whereas RhoA elicits axonal and dendritic retraction and spine/synapse loss (Luo, 2000;Mulherkar et al, 2017).…”

“…In autism, inhibition of RhoA rescued dendrite length and network activity phenotypes (Amar et al, 2021). Finally, dysregulation of Rho GTPases plays critical roles in neurodegenerative disorders, including Alzheimer's disease (Duman et al, 2021). Several transcription factors have been shown to regulate RhoA expression, including c-Myc, Max, and SMAD4 (mothers against decapentaplegic homolog 4) (Schmidt et al, 2022).…”