THE RHO GTPASE-CYTOSKELETON AXIS: A CHECKPOINT FOR MICROGLIAL HOMEOSTASIS AND SYNAPTIC RESILIENCE

Microglia, the brain's primary immune cells, maintain central nervous system (CNS) homeostasis through continuous environmental surveillance and intricate crosstalk with synapses. This dynamic function is fundamentally dependent on precise regulation of the actin cytoskeleton, a process orchestrated by the Rho family of GTPases, including Rac1 and RhoA, and actin-binding proteins like Profilin 1 (Pfn1). Disruptions in these pathways are increasingly linked to microglial dysfunction and neurodegenerative pathologies.
Microglial Pfn1 expression decreases with age in humans, and its acute loss in adult mice collapses cytoskeletal dynamics, impairing responses to brain injury and inducing a cell-autonomous, senescence-associated secretory phenotype (SASP) via the ERK/NF-κB axis. This senescent profile reprograms the synaptic environment, leading to mitochondrial energy deficits and selective reduction in GABAergic inhibitory postsynaptic currents, ultimately driving anxiety-like behaviors.
Complementary studies on specific Rho GTPases show that: Microglial Rac1 is essential for morphodynamic plasticity and experience-dependent synaptic remodeling - its ablation disrupts microglia-synapse communication and impairs learning, memory, and sociability, suggesting it is a key regulator of cognitive performance; and RhoA acts as a critical negative regulator of microglial immune activation - its loss leads to microglial dysregulation, neuronal dysfunction, and features of Alzheimer's disease pathology.
Understanding how this complex cytoskeletal signaling network regulates microglial resilience, might be relevant to enhance brain health and mitigate age-related neurodegeneration.
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