Rap1-Dependent pathways in depression: Genetic, Epigenetic, and neuroinflammatory mechanisms shaping synaptic...

Rap1, a small GTPase integral to synaptic plasticity, has emerged as a pivotal regulator in the pathophysiology of depression, bridging molecular, genetic, and environmental mechanisms. This review synthesizes evidence highlighting Rap1's role in long-term depression (LTD) and dendritic spine remodeling, where isoform-specific interactions (Rap1 vs. Rap2) modulate AMPA receptor trafficking and synaptic resilience. Genetic studies implicate Rap1-associated pathways, such as DOCK2 and DIRAS2, in postpartum depression, while postmortem analyses reveal reduced Rap1 activity in mood-related brain regions of depressed individuals. Epigenetic regulation, particularly stress-induced FTO downregulation, disrupts Rap1-dependent synaptic protein translation, linking environmental stressors to maladaptive plasticity. Neuroimmune crosstalk further underscores Rap1's dual role in synaptic and inflammatory signaling, as seen in comorbid depression and atopic dermatitis. Environmental toxins like cadmium dysregulate Rap1 via oxidative stress and epigenetic modifications, while phytocannabinoids modulate Rap1-ERK pathways to enhance neuroprotection. Therapeutic strategies, including vortioxetine and natural compounds like Modified Xiaoyaosan, target Rap1 to restore synaptic homeostasis. Emerging pathways, such as circadian disruptions and gut-brain axis interactions, suggest novel mechanisms by which Rap1 integrates systemic and neuronal stress responses. Unresolved questions persist regarding Rap1 isoform specificity, spatiotemporal regulation, and glial-neuronal metabolic coupling, necessitating advanced tools like biosensors and organoid models to unravel its pleiotropic roles in depression.