Effects of post-stress corticosterone on hippocampal excitability and behavior involving hyperpolarization-activated cation channel 1 function

Abstract Single Prolonged Stress (SPS) is a widely used rodent model for investigating the consequences of acute traumatic stress, but outcomes in mice are often variable across strains and behavioral domains. Because corticosterone (CORT) release is a central feature of the stress response, we combined SPS with post-stress CORT administration (SPS + CORT) to capture this hormonal component and unmask latent phenotypes. Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are highly expressed in the dorsal CA1 (dCA1) hippocampus, where they regulate neuronal excitability. We previously demonstrated that acute CORT enhances hyperpolarization-activated current ( I h ) in vitro; here, we tested its in vivo contribution to stress-related behavioral and physiological outcomes. Male mice (8–9 weeks old) were exposed to SPS followed by vehicle or CORT. Behavioral assays—including the open field, Y-maze, and contextual fear conditioning—revealed that SPS + CORT mice displayed impaired spatial working memory and deficits in contextual recall and fear extinction, resembling core PTSD-like features. Whole-cell recordings from dCA1 neurons showed decreased input resistance, reduced action potential firing, and elevated I h , which were normalized by the HCN channel blocker ZD7288. Overexpression of HCN1 in SPS mice reproduced both behavioral and physiological phenotypes seen in SPS + CORT mice, whereas genetic deletion of HCN1 in SPS + CORT mice reduced I h and rescued the behavioral abnormalities. Together, these findings identify HCN1 channels as a critical mediator linking post-stress glucocorticoid signaling to maladaptive hippocampal plasticity and PTSD-like outcomes.