The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus

Abstract

Rapastinel (GLYX-13) is an N-methyl-D-aspartate receptor (NMDAR) modulator that has characteristics of a glycine site partial agonist. Rapastinel is a robust cognitive enhancer and facilitates hippocampal long-term potentiation (LTP) of synaptic transmission in slices. In human clinical trials, rapastinel has been shown to produce marked antidepressant properties that last for at least one week following a single dose. The long-lasting antidepressant effect of a single dose of rapastinel (3 mg/kg IV) was assessed in rats using the Porsolt, open field and ultrasonic vocalization assays. Cognitive enhancement was examined using the Morris water maze, positive emotional learning, and contextual fear extinction tests. LTP was assessed in hippocampal slices. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex. Significant antidepressant-like or cognitive enhancing effects were observed that lasted for at least one week in each model. Rapastinel facilitated LTP 1 day – 2 weeks but not 4 weeks post-dosing. Biweekly dosing with rapastinel sustained this effect for at least 8 weeks. A single dose of rapastinel increased the proportion of whole-cell NMDAR current contributed by NR2B-containing NMDARs in the hippocampus 1 week post-dosing, that returned to baseline by 4 weeks postdosing. The NMDAR antagonist CPP blocked the antidepressant-like effect of rapastinel 1 week post dosing. A single injection of rapastinel also increased mature spine density in both brain regions 24 hrs post-dosing. These data demonstrate that rapastinel produces its long-lasting antidepressant effects via triggering NMDAR-dependent processes that lead to increased sensitivity to LTP that persist for up to two weeks. The data also suggest that these processes led to the alterations in dendritic spine morphologies associated with the maintenance of long-term changes in synaptic plasticity associated with learning and memory.

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

“…A recent report demonstrates that GLYX-13 also causes a rapid increase in the number of spine synapses in the PFC (Burgdorf et al, 2015a). The ability of rapid-acting antidepressants to cause fast release of BDNF in primary neuronal cultures is consistent with the possibility that these agents stimulate dendrite complexity.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Importantly, GLYX-13 reverses chronic stress-induced reduction in NMDAR-dependent LTP [217], which is a mechanism hypothesized to mediate its antidepressant actions. Moreover, similar to ketamine, GLYX-13 enhances hippocampal LTP in brain slices taken 24 h and 7 days following a single in vivo injection in rodents [218]. …”

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

“…However, the antidepressant actions of both GLYX-13 and ketamine are blocked by pretreatment with an AMPA receptor antagonist, indicating a requirement for glutamate-AMPA receptor activity (Burgdorf et al, 2013;Li et al, 2010;Maeng et al, 2008) 4 We have previously demonstrated that ketamine increases synaptic number and function in the mPFC, and shown that these effects depend on mTORC1 signaling (Li et al, 2010;Li et al, 2011). GLYX-13 is reported to enhance neuroplasticity suggesting that it may also enhance synaptic function (Burgdorf et al, 2015a(Burgdorf et al, , 2015b). In the current study, we compared the influence of GLYX-13 and ketamine on the mTORC1-signaling pathway and on the number and function of spine synapses in the rat mPFC.…”