Corticosterone-Induced Depression in Rats: Region-Specific and Time-Dependent Dysregulation of Glutamatergic Signaling, Synaptic Markers, and MMP-2 Expression.

Chronic corticosterone (CORT) exposure in rodents is a validated model for major depressive disorder (MDD). We examined behavioral and molecular effects of repeated CORT administration and recovery in male Wistar rats. Animals received daily subcutaneous injections of CORT (40 mg/kg) or vehicle for 21 days and were evaluated immediately (CORT group) or after 7 days (CORT/RE). Behavioral assessments included the open field test (OFT), Y-maze (YM), and forced swim test (FST). Molecular analyses targeted the hippocampus and hypothalamus by RT-qPCR for Nr3c1 (GR), Nr3c2 (MR), Grin1 (NR1), and Dlg4 (PSD-95), and by immunofluorescence for NR2B, PSD-95, and MMP-2. CORT caused sustained weight loss, adrenal atrophy, and increased immobility in the FST, persisting after discontinuation without cognitive or locomotor deficits. At the molecular level, Grin1 and Dlg4 mRNA expression were reduced in the hypothalamus. NR2B protein increased in the dentate gyrus (DG) and CA3 during CORT exposure but returned to baseline after discontinuation. PSD-95 decreased in DG and CA1, with partial recovery. Notably, MMP-2 remained elevated in the dentate gyrus after CORT cessation, suggesting ongoing extracellular matrix changes that may contribute to sustained synaptic remodeling. These findings support the chronic CORT model as a paradigm of sustained depressive-like behavior and neuroplastic alterations. Persistent MMP-2 upregulation points to enduring stress-induced synaptic dysfunction, highlighting molecular features relevant to depression. Thus, this model provides a translational framework to probe HPA axis dysregulation, behavioral despair, and synaptic remodeling, paralleling key aspects of MDD.