Abstract
Ketamine has been found to have rapid, long-lasting antidepressant effects in treatment-resistant (TR) patients with major depressive disorder (MDD). Recently, we have also shown that ketamine acts as a prophylactic to protect against the development of stress-induced depressive-like behavior in mice, indicating that a preventative treatment against mental illness using ketamine is possible. While there is significant investigation into ketamine’s antidepressant mechanism of action, little is known about ketamine’s underlying prophylactic mechanism. More specifically, whether ketamine’s prophylactic action is molecularly similar to or divergent from its antidepressant action is entirely unknown. Here, we sought to characterize immunohistochemical signatures of cell populations governing ketamine’s antidepressant and prophylactic effects. 129S6/SvEv mice were treated with saline (Sal) or ketamine (K) either before a social defeat (SD) stressor as a prophylactic, or after SD as an antidepressant, then subsequently assessed for depressive-like behavior. Post-fixed brains were processed for doublecortin (DCX), calretinin (CR) and calbindin (CB) expression. The number of DCX+ neurons in the dentate gyrus (DG) of the hippocampus (HPC) was not affected by prophylactic or antidepressant ketamine treatment, while the number of CR+ neurons in the ventral hilus increased with antidepressant ketamine under SD conditions. Moreover, antidepressant, but not prophylactic ketamine administration significantly altered CR and CB expression in the ventral HPC (vHPC). These data show that while antidepressant ketamine treatment mediates some of its effects via adult hippocampal markers, prophylactic ketamine administration does not, at least in 129S6/SvEv mice. These data suggest that long-lasting behavioral effects of prophylactic ketamine are independent of hippocampal DCX, CR and CB expression in stress-susceptible mice.
Highlights
Major depressive disorder (MDD) is one of the most prevalent and pervasive mental illnesses to date, affecting roughly 17% of the United States population (Kessler et al, 2005)
We investigated the Ca2+ binding protein CR, which is expressed in axonal arborizations of the inner molecular layer (IML) along the dorsoventral axis of the dentate gyrus (DG) (Volz et al, 2011)
We found that antidepressant, but not prophylactic, ketamine administration significantly altered CR and CB expression in the ventral HPC (vHPC), while DCX expression was not affected by either treatment
Summary
Major depressive disorder (MDD) is one of the most prevalent and pervasive mental illnesses to date, affecting roughly 17% of the United States population (Kessler et al, 2005). Selectively increasing the number of adult born neurons in the HPC using a transgenic mouse model is sufficient to reduce anxiety-like and depressive-like behaviors in stressed mice (Hill et al, 2015) This suggests a critical role for the integrity of SGZ neurons in MDD pathogenesis. Inhibition of ∆FosB, a transcription factor implicated in stress resilience, by viral expression of ∆JunD in ventral CA3 (vCA3) impairs the behavioral effects of prophylactic ketamine (Mastrodonato et al, 2018), suggesting the vHPC is necessary for eliciting a resilient phenotype following stress exposure Taken together, these data show that there may be specific brain circuits dedicated to MDD pathogenesis and recovery, which could potentially be targeted with ketamine treatment. A comparative investigation into the neurochemical origins governing ketamine’s bifold behavioral effects may advance targeted development of ketamine-driven interventions for psychiatric illnesses
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