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. 2015 Nov 12;308:202-11.
doi: 10.1016/j.neuroscience.2015.09.004. Epub 2015 Sep 4.

The Long-Lasting Antidepressant Effects of Rapastinel (GLYX-13) Are Associated With a Metaplasticity Process in the Medial Prefrontal Cortex and Hippocampus

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Free PMC article

The Long-Lasting Antidepressant Effects of Rapastinel (GLYX-13) Are Associated With a Metaplasticity Process in the Medial Prefrontal Cortex and Hippocampus

J Burgdorf et al. Neuroscience. .
Free PMC article

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 (3mg/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 1day-2weeks but not 4weeks post-dosing. Biweekly dosing with rapastinel sustained this effect for at least 8weeks. A single dose of rapastinel increased the proportion of whole-cell NMDAR current contributed by NR2B-containing NMDARs in the hippocampus 1week post-dosing, that returned to baseline by 4weeks post-dosing. The NMDAR antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked the antidepressant-like effect of rapastinel 1week post dosing. A single injection of rapastinel also increased mature spine density in both brain regions 24h 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. These 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.

Keywords: GLYX-13; LTP; NMDA receptor; depression; hippocampus; medial prefrontal cortex.

Figures

Fig 1
Fig 1. A single dose of rapastinel (3 mg/kg IV) produces antidepressant-like effects in multiple models 1 week post-dosing
Male 2–3 month old Sprague Dawley rats were pretreated with a single dose of rapastinel (TPPT-NH2; 3 mg/kg IV) or sterile saline vehicle (0.9%, 1 ml/kg) and were tested 1 week post-dosing in the following behavioral paradigms: (A) Porsolt forced swim test with floating time (sec) quantified during the 5 min test; (B) open field test with total number of line crosses and time (sec) spent in the center compartment of the open field being measured during the 10 min test; (C) ultrasonic vocalization (USVs) test with total hedonic and aversive USVs measured during the 3 min test session. N = 11 rats per group. Mean ± SEM * P < .05 ANOVA, rapastinel vs. vehicle.
Fig 2
Fig 2. A single dose of rapastinel (3 mg/kg IV) facilitates learning and memory in multiple models 1 day to 1 week post-dosing
Male 2–3 month old Sprague Dawley rats were pretreated with a single dose of rapastinel (3 mg/kg IV) or sterile saline vehicle (0.9%, 1 ml/kg) and received a single tests session 1 week post dosing (A–B) or were dosed 24 hrs before the first of 5 (C) or 6 (D) daily test sessions: (A) % of alternating trials in the spontaneous alternating closed arm plus maze test; (B) hedonic ultrasonic vocalizations in response to a conditioned stimuli that predicts heterospecific play in the USVs test; (C) path length to find the hidden platform in the movable platform version of the Morris water maze test; (D) % freezing during contextual fear extinction. N = 8–21 rats per group. Mean ± SEM (a) * P < .05 within subjects t-test, 2 tailed, (B–D) * P < .05 Fisher’s PLSD post hoc test rapastinel vs. vehicle.
Fig 3
Fig 3. Rapastinel enhances hippocampal LTP 24 h and 1 week following a single dose, and persistently enhances LTP following multiple doses every 2 weeks
A single in vivo dose of rapastinel (3 mg/kg IV; filled blue circles) in 2–3 month old male SD rats significantly enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission compared to vehicle treated controls (open black circles), tested in vitro (A) 24 hrs and (B) 1 week post-dosing at Schaffer collateral-CA1 synapses after 1, 2 and 3 sub-maximal high-frequency stimulus trains (2×100Hz/800ms, arrows, P < .05, Fisher’s PLSD post hoc test), but not (C) 2 or (D) 4 weeks post-dosing (P >.05). In contrast, short-term potentiation (STP) 5 min after the first high frequency stimulus was significantly increased at all timepoints from 24 hrs to 4 weeks post-dosing (P < .05, Fisher’s PLSD post hoc test). Repeated dosing once every 2 weeks for up to 8 weeks with rapastinel produced sustained enhancement of both LTP and STP measured 24 hrs after the final dose (E–H, filled blue circles, P < .05; Fisher’s PLSD post hoc test), which reversed by 4 weeks following the final dose (H, open blue circles, P > 0.05, Fisher’s PLSD post hoc test). N = 5–9 slices per group.
Fig 4
Fig 4. Rapastinel persistently increases the NR2B component of NMDAR conductances for 1 week post-dosing, and the NMDAR antagonist CPP blocks the antidepressant-like effect of rapastinel 1 week post-dosing
(A) Mean ± SEM fraction of blockade of NMDAR-mediated EPSCs by the NR2B-selective blocker Ro25-6981 (1µM), in control (0 mg/kg; N=8) CA1 pyramidal neurons, versus neurons in slices from rats treated one week (1 W; N=7) or 4 weeks (4 W; N=10) earlier with 3 mg/kg Rapastinel. Right panel: Representative EPSCs recorded from CA1 pyramidal neurons in slices prior to drug treatment (black traces), in the presence of the NR2B-selective NMDAR antagonist 1µM Ro25-6981 (red traces) and in the presence of 1µM Ro25-6981 plus the NR2A-selective NMDAR antagonist 10µM TCN-213 (blue traces). Ro25-6981 + TCN-213 blocked 79% of all current and did not differ between groups (results section). (B) Mean (±SEM) floating time in the Porsolt forced swim test in 2–3 month old male SD rats pretreated with rapastinel (3 mg/kg IV; or saline vehicle IV) 1 week before administration of the NMDAR receptor antagonist CPP (10 mg/kg IP; or saline vehicle IP) and tested 1 hr post CPP administration. Testing consisted of a single 5 min swim session, and the animals were given a 15 min habituation swim session 24 hrs before testing (N = 9 per group. * P < .05 Fisher’s PLSD post hoc test vs. all other groups).
Fig 5
Fig 5. A single dose of rapastinel (3 mg/kg IV) induces increases in mature spines in distal dendrites of the dentate gyrus and Layer 5 of the MPFC 24 hrs post-dosing
In male 2–3 month old rats, rapastinel (3 mg/kg IV, in blue) significantly increased (A) the proportion of mature dendritic spines in the dentate gyrus (primary apical, 100–150 µM from the dendrite) or MPFC layer 5 tufts, and increased (C) the density (spines/10 µM of dendrite) of stubby spines in both regions. Rapastinel also decreased (B) % of immature spines (thin spines) and (E) the density of thin spines only in the dentate gyrus. Rapastinel did not alter (D) mushroom spines or (F) total spine density in these same regions. Representative laser-scanning confocal micrographs of layer 5 MPFC dendrites from rapastinel and vehicle treated animals are shown in panel (G) Mean ± SEM. N = 15 cells/per group (n = 3 rats per group; ~ 13,125 dendrites/group), * P < .05 Fisher’s PLSD post hoc test.

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