The novel antidepressant ketamine enhances dentate gyrus proliferation with no effects on synaptic plasticity or hippocampal function in depressive‐like rats

Abstract

Aim:Major depressive disorder is a common and debilitating condition with substantial economic impact. Treatment options, although effective, are aimed at relieving the symptoms with limited disease modification. Ketamine, a commonly used anaesthetic, has received substantial attention as it shows rapid antidepressant effects clinically. We studied the effects of ketamine on hippocampal function and dentate gyrus proliferation in rats showing a depressive-like phenotype. Methods: Adolescent and adult animals were pre-natally exposed to the glucocorticoid analog dexamethasone, and we verified a depressive-like phenotype using behavioural tests, such as the sucrose preference. We subsequently studied the effects of ketamine on hippocampal synaptic transmission, plasticity and dentate gyrus proliferation. In addition, we measured hippocampal glutamate receptor expression. We also tested the ketamine metabolite hydroxynorketamine for NMDA-receptor independent effects. Results: Surprisingly, our extensive experimental survey revealed limited effects of ketamine or its metabolite on hippocampal function in control as well as depressivelike animals. We found no effects on synaptic efficacy or induction of long-term potentiation in adolescent and adult animals. Also there was no difference when comparing the dorsal and ventral hippocampus. Importantly, however, ketamine 24 hours prior to experimentation significantly increased the dentate gyrus proliferation, as revealed by Ki-67 immunostaining, in the depressive-like phenotype. Conclusion: We find limited effects of ketamine on hippocampal glutamatergic transmission. Instead, alterations in dentate gyrus proliferation could explain the antidepressant effects of ketamine.

Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine

“…In contrast, Choi et al (2016) reported that ketamine fails to enhance cell differentiation or maturation into neurons, although ketamine accelerates cell proliferation in the DG. Moreover, Michaelsson et al (2019) reported that ketamine increases the DG proliferation and exerts no effect on synaptic efficacy or induction of long-term potentiation in both dorsal and ventral hippocampus. Together these studies indicate that neurogenesis could be involved in the sustained but not rapid actdions of ketamine, although additional studies needed to further examine this question.…”

<p>Ketamine in Bipolar Disorder: A Review</p>

“…[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]121 There is some evidence for the modifying effects of ketamine on epigenetic processes present in BD, [64][65][66][67][68][69][70] as well as its ability to regulate inflammation. [62][63][64][65][66][67][68][69] Ketamine may also have favorable effects on gut microbiota, which have been shown to be disturbed in patients with BD. [71][72][73][74][75][76][77][78] The majority of the above-mentioned effects, however, are based on preliminary evidence and engage unipolar depression model, and therefore require confirmation by studies in bipolar disorder.…”

“… 61 However, some studies have shown contrary evidence and do not support the beneficial effect of ketamine on synaptic plasticity and the proliferation of neurons in rats. 62 , 63 Taken together, it is likely that neurogenesis could have a role in the sustained actions of ketamine; nevertheless, this remains to be confirmed by future studies.…”

17β-Estradiol Protects Neural Stem/Progenitor Cells Against Ketamine-Induced Injury Through Estrogen Receptor β Pathway

“…Ketamine inhibited the activity of macrophages and the production of pro-inflammatory cytokines ( Chang et al, 2016 ). Pain and surgery-related psychological stress induce harmful neurobiological effects on immature brain, which is related to brain development damage and long-term behavioral consequences ( Brummelte et al, 2012 ; Michaelsson et al, 2019 ). Ketamine can reduce neuronal activation and cell death in cortex and subcortical area of neonatal rats caused by inflammatory pain ( Liu et al, 2012 ).…”