TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response

Abstract

Adult neurogenesis persists in the rodent dentate gyrus and is stimulated by chronic treatment with conventional antidepressants through BDNF/TrkB signaling. Ketamine in low doses produces both rapid and sustained antidepressant effects in patients. Previous studies have shed light on post-transcriptional synaptic NMDAR mediated mechanisms underlying the acute effect, but how ketamine acts at the cellular level to sustain this anti-depressive function for prolonged periods remains unclear. Here we report that ketamine accelerates differentiation of doublecortin-positive adult hippocampal neural progenitors into functionally mature neurons. This process requires TrkB-dependent ERK pathway activation. Genetic ablation of TrkB in neural stem/progenitor cells, or pharmacologic disruption of ERK signaling, or inhibition of adult neurogenesis, each blocks the ketamine-induced behavioral responses. Conversely, enhanced ERK activity via Nf1 gene deletion extends the response and rescues both neurogenic and behavioral deficits in mice lacking TrkB. Thus, TrkB-dependent neuronal differentiation is involved in the sustained antidepressant effects of ketamine.

Searching for ketamine's antidepressant mechanisms: From synaptic plasticity to dentate gyrus cell proliferation

“…Ketamine (or HNK) had no impact on cell proliferation when directly applied on isolated hippocampal stem cells. This paper together with other recent findings thus link the antidepressant effects of ketamine into hippocampal cell proliferation, differentiation and neurogenesis, which are already associated with the mechanism of action of traditional monoaminergic antidepressants.…”

Ketamine Alleviates Postoperative Depression-Like Symptoms in Susceptible Mice: The Role of BDNF-TrkB Signaling

“…It has been recognized that age and sex differences are the triggering factors in the incidence of depression and postoperative complications (Luppa et al, 2012). In this study, sex and age differences failed to show statistical changes impacting the POD incidence although there was a slight difference between the groups.…”

TrkB neurotrophin receptor at the core of antidepressant effects, but how?

“…Ketamine and positive allosteric modulators of AMPA-Rs upregulate immediate early gene expression, including the bdnf. Moreover, ketamine has been shown to increase local translation of BDNF and activation of TrkB receptor in the rodent prefrontal cortex and hippocampus (Autry et al 2011;Monteggia et al 2013;Yang et al 2015Yang et al , 2016Carreno et al 2016;Sun et al 2016;Dong et al 2017;Ma et al 2017) (Fig. 1).…”