Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures

Abstract

Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABAA receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 hr increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.

Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

“…The rapid antidepressant effects of the ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker ketamine were shown to require BDNF and pathways downstream of its high-affinity receptor TrkB, and to require protein synthesis but not transcription, suggesting that BDNF may be locally translated in and secreted from dendrites (Autry et al 2011; Lepack et al 2016; Lepack et al 2014; Lepack et al 2015). Similar to ketamine, the antidepressant actions of GLYX-13, a novel glutamatergic compound and NMDA modulator with glycine-like partial agonist properties (Kato et al 2017), and scopolamine, a nonselective muscarinic acetylcholine receptor antagonist (Ghosal et al 2018), may also mechanistically depend on rapid desuppression of translation of select mRNAs (e.g.…”

“…Localized changes in synaptic plasticity that increase the activity of specific synapses and neural circuits occur in response to administration of rapid-acting antidepressants, including ketamine (Lepack et al 2016; Lepack et al 2014; Lepack et al 2015), GLYX-13 (Kato et al 2017; Liu et al 2017), scopolamine (Ghosal et al 2018), and the VGF peptide TLQP-62 (Jiang et al 2017; Li et al 2017; Lin et al 2014). It has been proposed that these changes are regulated by local translation and activity-dependent release of BDNF (Leal et al 2013; Santos et al 2010; Waterhouse and Xu 2009), and by VGF and VGF-derived C-terminal neuropeptides (Jiang et al 2017) (Figure 1).…”

Rapid-Acting Antidepressants: Mechanistic Insights and Future Directions

“…Recent preclinical work has explored antidepressant models and found that a single dose of GLYX-13 is sufficient to produce a rapid antidepressant response, including reversal of anhedonia resulting from chronic unpredictable stress exposure [51, 52]. Similar to ketamine, GLYX-13 increases spine synapse formation in the PFC, and its antidepressant effects are AMPAR-, BDNF-, and mTORC1-dependent [51, 53, 54]. However, unlike ketamine, GLYX-13 does not influence responding in prepulse inhibition or conditioned place preference, or 5-HT 2A induced head-twitch response of impulsivity in a serial reaction time task [51].…”

Modulation of the activity of <em>N</em>-methyl-D-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13)

“…Similar to ketamine, rapastinel rapidly increases levels of the phosphorylated and activated forms of the extracellular signal-regulated kinase (ERK) and a downstream target of mTORC1 as well as promotes an elevated BDNF release in rat primary cortical culture neurons 63. This induction of BDNF release and stimulation of phospho-ERK could be experimentally blocked by incubation with an AMPAR antagonist 63. In vitro incubation with rapastinel for 24 hours increased the number and length of neuronal branches, suggesting a neuroplastic effect and higher neuronal complexity triggered by this drug 63.…”

“…This induction of BDNF release and stimulation of phospho-ERK could be experimentally blocked by incubation with an AMPAR antagonist 63. In vitro incubation with rapastinel for 24 hours increased the number and length of neuronal branches, suggesting a neuroplastic effect and higher neuronal complexity triggered by this drug 63. In addition, rapastinel was shown to significantly reverse the changes induced by chronic unpredictable mild stress in the expression of several signaling molecules associated with depression, including AKT, mTOR and eEF2 kinase in the hippocampus 64.…”