Major depressive disorder (MDD) is a significant global health concern, with current antidepressants often exhibiting delayed onset and limited efficacy. Ketamine, while effective in rapidly alleviating depressive symptoms, carries substantial risks. The mechanisms underlying ketamine's rapid antidepressant effects remain unclear. While ketamine is an NMDA receptor antagonist, this alone doesn't fully explain its effects, suggesting involvement of other pathways. Some proposed mechanisms include its metabolites, altered signaling pathways (increased BDNF, mTOR activation, AMPA receptor activation), and effects on hippocampal circuitry. The hippocampus is implicated in MDD, and its volume is reduced in patients. Conventional antidepressants increase adult hippocampal neurogenesis, but this process takes weeks, unlike ketamine's rapid action. Previous studies suggested acute activation of ABINs in the dentate gyrus (DG) might be involved in ketamine's rapid effects. This study investigates whether ABIN activity is necessary and sufficient for ketamine's rapid antidepressant effects using a chemogenetic approach.

Extensive research has explored the mechanisms of action of antidepressants, highlighting the slow onset of conventional treatments and the need for faster-acting alternatives. Ketamine's rapid antidepressant effects have spurred investigation into its various mechanisms of action, including its impact on NMDA receptors, its metabolites, and its influence on intracellular signaling pathways such as BDNF and mTOR. The role of the hippocampus in depression and the effects of antidepressants on hippocampal neurogenesis have been extensively studied. However, the acute effects of ketamine seem to be independent of the slower neurogenesis process. Prior studies suggested a possible link between the rapid antidepressant action of ketamine and the activation of ABINs in the dentate gyrus.

The study employed several methodologies. First, the behavioral effects of ketamine (3 mg/kg, i.p. injection) were assessed in wild-type C57BL/6 mice using social interaction (SIT), social novelty (SNT), and tail suspension (TST) tests. Next, immunohistochemistry was used to analyze the expression of immediate-early genes (c-Fos and EGR1) in the DG to determine neuronal activity following ketamine treatment. To identify the specific neuronal population involved, co-staining with markers of neuronal maturity (NeuroD1, NeuroD2, Calbindin) was performed. A chemogenetic approach, utilizing the Ascl1-Cre/hM4Di mouse model, was used to inhibit ABIN activity in the DG. The effects of ABIN inhibition on ketamine's behavioral effects were then assessed. A separate experiment using the Ascl1-Cre/hM3Dq mouse model allowed for chemogenetic activation of ABINs. The effects of ABIN activation on both behavior and neuronal activity were evaluated. The role of AMPA receptors in ketamine's effects was investigated using the AMPA receptor antagonist NBQX. The unpredictable chronic mild stress (UCMS) model was employed to assess the effects of ketamine and ABIN modulation in stressed mice. Statistical analysis included Student's t-tests and ANOVAs with post-hoc tests.

Ketamine treatment significantly increased sociability, preference for social novelty, and reduced immobility in both stressed and unstressed mice. Ketamine significantly increased the number of c-Fos and EGR1-activated neurons in the DG, primarily in immature neurons (EGR1+, NeuN+, Calbindin-). Chemogenetic inhibition of ABIN activity blocked ketamine's antidepressant-like behavioral effects. Chemogenetic activation of ABINs, without altering neuron numbers, mimicked ketamine's cellular and behavioral effects, increasing sociability, social novelty preference, and decreasing immobility. Ketamine's effects on ABINs and behavior were blocked by the AMPA receptor antagonist NBQX, indicating a dependence on AMPA receptor activity. In stressed mice, ketamine increased ABIN activity and rescued stress-induced behavioral deficits, which were again blocked by ABIN inhibition.

The findings strongly support the hypothesis that ABIN activity is both necessary and sufficient for ketamine's rapid antidepressant effects. The study successfully identifies a specific cellular mechanism, targeting ABINs, potentially providing a pathway for developing novel antidepressants with fewer side effects than ketamine. The dependence on AMPA receptor activity highlights another potential therapeutic target. The results may also explain the differential effectiveness of NMDA receptor antagonists, with only those facilitating ABIN activation showing rapid antidepressant effects. Further research could explore the specific signaling pathways within ABINs mediating ketamine's effects and the precise role of AMPA receptors in this process.

This study demonstrates that the activity of adult-born immature granule neurons in the dentate gyrus is critical for the rapid antidepressant effects of ketamine. Both inhibition and activation studies strongly support this conclusion. These findings suggest that targeting ABINs may offer a promising strategy for developing novel, rapid-acting antidepressants with reduced side effects. Future research should investigate the specific intracellular mechanisms involved and the role of AMPA receptors in mediating these effects.

The study was conducted in mice, and the findings may not directly translate to humans. The chemogenetic approach, while effective, might not perfectly replicate the natural effects of ketamine. Further research is needed to fully elucidate the specific signaling pathways involved and the long-term effects of ABIN modulation.