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

Single Prolonged Stress (SPS) is a widely used animal model for investigating the physiological and behavioral consequences of acute stress exposure. Glucocorticoids released during stress can induce atypical fear memories, including contextual amnesia and emotional hypermnesia. Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are abundantly expressed in the dorsal CA1 (dCA1) region of the hippocampus, where they influence both intrinsic neuronal excitability and synaptic function. Although we have previously shown that acute corticosterone (CORT) exposure increases hyperpolarization-activated current ( I _h ) in dCA1 neurons in vitro , it remains unclear whether in vivo CORT exposure following stress exerts similar effects and contributes to behavioral dysfunction. To address this, 8–9-week-old male mice were subjected to SPS followed by treatment with either vehicle or CORT. Behavioral assays—including the open field test, Y-maze, and contextual fear conditioning—were conducted, followed by whole-cell patch-clamp recordings in dCA1 neurons. Mice treated with SPS and post-CORT exhibited deficits in spatial working memory, contextual recall, and fear extinction, mimicking PTSD-like symptoms. Electrophysiological recordings revealed that dCA1 neurons from these mice displayed decreased input resistance, reduced action potential firing, and elevated I _h . These alterations were reversed by ZD7288, an HCN channel blocker. Moreover, overexpression of HCN1 in dCA1 neurons in SPS-treated mice reproduced both the behavioral and physiological phenotypes observed in the SPS-CORT group. Collectively, these findings suggest that post-stress CORT exposure promotes maladaptive hippocampal plasticity via enhanced HCN1 activity, linking stress hormones to altered hippocampal function and PTSD-like behavioral outcomes.