Role of CaMKII/CREB pathway in rapid-antidepressant-like effect: comparison of ketamine with rapastinel

Abstract

Recent studies in mouse models have demonstrated that ketamine and rapastinel induce rapid-acting and sustained antidepressant effects in major depressive disorder (MDD). However, it remains unclear how ketamine's and rapastinel's opposing mechanisms of action-NMDAR antagonist and NMDAR positive allosteric modulator, respectively-result in similar antidepressant-like effects. Furthermore, although the CaMKII/CREB pathway plays a crucial role in BDNF synthesis and synaptic plasticity, its involvement in rapastinel- or ketamine-induced antidepressant effects has not been studied in detail. The main purpose of this study was to analyze the link between BDNF levels and CaMKII/CREB activity in the antidepressant-like effects of rapastinel and ketamine treatments. This study used 46 male mice subjected to the chronic unpredictable mild stress (CUS) model for 28 days. Based on their experimental groups, the animals were administered the CaMKII inhibitor TatCN21 (5 mg/kg i.p.), ketamine (10 mg/kg i.p.), or rapastinel (3 mg/kg i.p.), either alone or in combination. Behavioral tests and molecular analyses were performed. The CUS model significantly reduced weight gain, decreased sucrose preference in the sucrose preference test (SPT), and increased immobility time in the forced swim test (FST) compared to the control group. BDNF concentrations in the prefrontal cortex (PFC) and hippocampus were significantly reduced following chronic stress. Both ketamine and rapastinel reduced anhedonia and passive coping behavior, demonstrating their antidepressant-like effects. Treatment with ketamine or rapastinel after chronic stress significantly increased BDNF concentrations in the PFC and hippocampus 24 h post-injection. Similarly, TatCN21 significantly increased BDNF levels in the PFC and hippocampus and reduced immobility time in the FST. Interestingly, when the CaMKII inhibitor was administered before ketamine or rapastinel, it had opposing effects on their antidepressant-like actions. TatCN21 enhanced rapastinel's effects while blocking the antidepressant-like effects of ketamine, suggesting that the CaMKII pathway may play a differential role in mediating these effects. Overall, this study provides insights into the potential mechanisms underlying the antidepressant-like effects of ketamine and rapastinel. Understanding these mechanisms could aid in developing new treatments for depression that are both rapid-acting and long-lasting, without the side effects associated with current medications.

Keywords: BDNF; CaMKII/CREB; Chronic stress; Depression; Ketamine; Rapastinel; Synaptic plasticity.