Our data indicate that during the development of comorbid depression, Tiam1 is activated in response to chronic pain–stimulated NMDARs in the ACC and links NMDARs to Rac1 activation that orchestrates synaptic structural plasticity via actin and spine remodeling and functional plasticity via synaptic NMDAR stabilization, which contributes to ACC hyperactivity and depressive-like behaviors. The gene discussed is TIAM1; the disease is major depressive disorder.