Rho GTPase Signaling in Structural Plasticity and Dendritic Spine Remodeling

Structural plasticity, the physical reshaping of dendritic spines, is the anatomical correlate of long-term information storage. The dynamics of the actin cytoskeleton are the primary driver of these morphological changes, and the Rho family of small GTPases—RhoA, Rac1, and Cdc42—serves as the master regulator of this process.

Rac1 and Cdc42 are potent inducers of actin polymerization. Upon activation by specific guanine nucleotide exchange factors, they stimulate the Arp2/3 complex to nucleate new actin filaments, leading to the formation of filopodia and the expansion of the spine head. This process is essential for the spine enlargement observed during long-term potentiation and new spine formation.

In direct opposition, RhoA activation promotes actinomyosin contractility. Through its downstream effector Rho-associated protein kinase, RhoA phosphorylates and activates LIM kinase, which in turn phosphorylates and inactivates the actin-depolymerizing factor cofilin. This leads to a stabilization of the actin cytoskeleton in a contracted state, resulting in spine shrinkage and retraction, hallmarks of long-term depression.

The balance between these pathways is exquisitely controlled by synaptic activity. For instance, calcium influx through NMDA receptors can activate calpain, which cleaves and inactivates the Rac1 guanine nucleotide exchange factor. This provides a direct link between calcium transients and the suppression of spine growth under certain conditions, favoring LTD.

Brain-Derived Neurotrophic Factor signaling is a key positive regulator of spine growth. Upon binding to its TrkB receptor, BDNF activates Rac1 via the guanine nucleotide exchange factor. This signaling cascade promotes the actin reorganization necessary for converting immature, filopodial-like protrusions into mature, mushroom-shaped spines, which are stable and highly synaptic.

Dysregulation of Rho GTPase signaling is a common pathological feature in several neurodevelopmental and psychiatric disorders. For example, mutations in genes encoding regulators of Rac1 and RhoA are linked to intellectual disability and autism spectrum disorders, highlighting the critical importance of precise spatial and temporal control over structural plasticity for proper cognitive function.