Pushing the threshold: How NMDAR antagonists induce homeostasis through protein synthesis to remedy depression

Abstract

Healthy neurons have an optimal operating range, coded globally by the frequency of action potentials or locally by calcium. The maintenance of this range is governed by homeostatic plasticity. Here, we discuss how new approaches to treat depression alter synaptic activity. These approaches induce the neuron to recruit homeostatic mechanisms to relieve depression. Homeostasis generally implies that the direction of activity necessary to restore the neuron’s critical operating range is opposite in direction to its current activity pattern. Unconventional antidepressant therapies deep brain stimulation and NMDAR antagonists alter the neuron’s “depressed” state by pushing the neuron’s current activity in the same direction but to the extreme edge. These therapies rally the intrinsic drive of neurons in the opposite direction, thereby allowing the cell to return to baseline activity, form new synapses, and restore proper communication. In this review, we discuss seminal studies on protein synthesis dependent homeostatic plasticity and their contribution to our understanding of molecular mechanisms underlying the effectiveness of NMDAR antagonists as rapid antidepressants. Rapid antidepressant efficacy is likely to require a cascade of mRNA translational regulation. Emerging evidence suggests that changes in synaptic strength or intrinsic excitability converge on the same protein synthesis pathways, relieving depressive symptoms. Thus, we address the question: Are there multiple homeostatic mechanisms that induce the neuron and neuronal circuits to self-correct to regulate mood in vivo? Targeting alternative ways to induce homeostatic protein synthesis may provide, faster, safer, and longer lasting antidepressants.

FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties

“…or saline for western blot analysis. The hippocampi were collected within the initiation phase (30 min post injection), a phase where molecular changes facilitate increased downstream mTORC1 activity 11 . Consistent with rapid antidepressants, acute ethanol injection increased the protein expression of GABA B R2 by ∼37% in the hippocampus with no significant change in GABA B R1 ( Fig.…”

“…Studies suggest that antidepressant efficacy requires two phases—an induction phase and a sustained phase 10 11 . Notably, GABA B R-mediated, mTORC1-dependent protein synthesis is required for the long-lasting sustained phase of rapid antidepressants.…”

Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances

“…Ketamine action in abstinence-associated negative affect While the specific anti-depressive mechanisms of ketamine and other rapid anti-depressants are being actively investigated (for review see: [34][35][36]), pre-clinical studies have suggested that antagonism of GluN2B containing NMDARs with Ro-25-6981 decreases depressive-like behavior in the force swim test [16,37,38], NSFT [31,37,38], and novelty-induced hypophagia [22]. In addition, another GluN2B-NMDA receptor antagonist, ifenprodil, has been shown to reverse chronic unpredictable stress-induced sucrose preference deficits [39].…”

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…Figure 24 represents this possible explanation for how the hypothesis of over-inhibition in the PFC fits with reports of GABAergic deficits in stress and affective dysfunction, though this remains to be tested. It has been suggested that rapid-acting antidepressants like ketamine re-engage homeostatic plasticity to elevate both glutamatergic and GABAergic systems again and restore proper E/I balance (Raab-Graham et al, 2016;Workman et al, 2018). In support of this idea, mice deficient for the γ2 subunit of the GABAAR, which show emotional dysfunction, show suppressed glutamatergic and GABAergic system activity, both of which are restored by ketamine treatment (Ren et al, 2016).…”