Antidepressant but Not Prophylactic Ketamine Administration Alters Calretinin and Calbindin Expression in the Ventral Hippocampus

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.

Hippocampal Subgranular Zone FosB Expression Is Critical for Neurogenesis and Learning

“…ΔFosB accumulation in the dHPC results in a number of downstream changes in gene expression, including epigenetic alterations at target genes. Of note is histone deacetylation at the Calb1 gene, a calcium binding protein and marker of mature neurons (Corbett BF et al, 2017;LaGamma CT et al, 2018;You JC et al, 2017;You JC et al, 2018), whose regulation by ΔFosB may be critical for the altered neurogenesis we report in FosB SGZ knockout. Alternatively, ΔFosB may directly regulate microglia through C5aR1 and C5aR2 (Nomaru H et al, 2014), and this in turn may elicit the altered neurogenesis we report in FosB SGZ knockout (Rivera PD et al, 2018).…”

Short Daily Exposure to Environmental Enrichment, Fluoxetine, or Their Combination Reverses Deterioration of the Coat and Anhedonia Behaviors with Differential Effects on Hippocampal Neurogenesis in Chronically Stressed Mice

“…Similarly, the administration of ketamine to socially defeated 129S6/SvEv mice produced increasing numbers of calretinin-positive cells in the ventral hippocampus [67]. These data suggest that increased cell proliferation with the consequent increase in the number of calretinin cells may be relevant to mediate the effects of FLX.…”

NRSF deficiency leads to abnormal postnatal development of dentate gyrus and impairment of progenitors in subgranular zone of hippocampus

“…In adult‐hippocampal neurogenesis, doublecortin (DCX), calretinin (CR), and calbindin (CB) are sequentially expressed at different developmental stages (LaGamma et al, 2018a, 2018b; Todkar, Scotti, & Schwaller, 2012; Volz et al, 2011). The analysis of these markers revealed that NRSF‐cKO mice had significantly lower DCX expression at P35 and P90, as well as a reduction of CR+ cells in SGZ (Figure 5a,b) at P16, P35, and P90.…”