Chronic Mild Stress in Male Wistar‐Kyoto Rats Induces Long‐Term Hippocampal Plasticity Impairments Differentially Reversed by Acute and Chronic Ketamine Treatment

Abstract

Chronic stress induces strong alteration of hippocampal synaptic plasticity, impairing long-term potentiation and facilitating long-term depression, processes thought to be involved in the pathophysiology of depression. Ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate receptor, has emerged as a fast-acting antidepressant whose action is believed to involve restoring impaired plasticity, though its sustained effects are elusive. Here, we investigated how chronic mild stress and subsequent acute and chronic ketamine treatments modulate synaptic plasticity in the Schaffer collateral pathway in the dorsal hippocampus of stress-vulnerable Wistar-Kyoto rats. Adult male rats were subjected to 4 weeks of chronic mild stress and vulnerability was determined through behavioral performance in the forced swim and elevated plus maze tests. Stress-vulnerable rats received saline or either an acute or chronic subanesthetic dose of ketamine (10 mg/kg), and hippocampal slices were harvested for synaptic plasticity investigation. Conversely to what occurred in nonstressed rats, in stress-vulnerable rats treated with saline, neither long-term potentiation (LTP) nor long-term depression (LTD) could be induced following high-frequency and low-frequency stimulation, respectively. Acute ketamine restored normal LTP but not LTD, while chronic ketamine restored LTD but not LTP. These findings highlight complex temporal dynamics in the modulation of hippocampal synaptic plasticity by ketamine following chronic stress and demonstrate that acute and chronic treatment regimens differentially affect the induction of LTP and LTD.