Reduction in membrane AMPA receptor subunit 2 in left prefrontal cortex correlates with post-stroke depression

Post-stroke depression (PSD) is a prevalent and debilitating complication of stroke. While ischemic lesion in left prefrontal cortex (PFC) is a recognized risk factor, the underlying mechanisms linking this locus to PSD remain poorly defined. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit 2 (GluA2) plays a critical role in neuroplasticity and mood regulation. In this study, a PSD rat model was used to investigate the pathophysiological mechanisms in left PFC through behavioral testing, biochemical assays, and pharmacological interventions targeting protein kinase C alpha (PKCα) and protein interacting with C kinase 1 (PICK1)-GluA2 binding. The results demonstrated that PSD reduced membrane GluA2 in left PFC. Mechanistically, PICK1 participated in the phosphorylation of GluA2 by PKCα, which in turn facilitated the reduction of membrane GluA2. Crucially, both inhibition of PKCα and disruption of PICK1-GluA2 binding rescued membrane GluA2 in left PFC without affecting total GluA2 expression and alleviated depressive-like behaviors of PSD rats. These findings suggest that reduced membrane GluA2 in left PFC correlates with PSD and may represent a potentially therapeutic target.