The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus.
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.
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, 1801 Maple Avenue, Suite 4300, Evanston, IL 60201, USA.
J
J
Burgdorf
Department of Cell Biology & Anatomy, Basic Sciences Building, Room 217, New York Medical College, Valhalla, NY 10595, USA.
X-L
XL
Zhang
Department of Physiology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward Building 7-140, Chicago, IL 60611, USA.
C
C
Weiss
Naurex Inc., 1801 Maple Avenue, Suite 4300, Evanston, IL 60201, USA.
A
A
Gross
Afraxis Inc., 11099 North Torrey Pines Road, Suite 290, La Jolla, CA 92037, USA.
S R
SR
Boikess
Naurex Inc., 1801 Maple Avenue, Suite 4300, Evanston, IL 60201, USA.
R A
RA
Kroes
Naurex Inc., 1801 Maple Avenue, Suite 4300, Evanston, IL 60201, USA.
M A
MA
Khan
Naurex Inc., 1801 Maple Avenue, Suite 4300, Evanston, IL 60201, USA.
R M
RM
Burch
Afraxis Inc., 11099 North Torrey Pines Road, Suite 290, La Jolla, CA 92037, USA.
C S
CS
Rex
Department of Physiology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Ward Building 7-140, Chicago, IL 60611, USA.
J F
JF
Disterhoft
Department of Cell Biology & Anatomy, Basic Sciences Building, Room 217, New York Medical College, Valhalla, NY 10595, USA.
P K
PK
Stanton
Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, 1801 Maple Avenue, Suite 4300, Evanston, IL 60201, USA; Naurex Inc., 1801 Maple Avenue, Suite 4300, Evanston, IL 60201, USA. Electronic address: j-moskal@northwestern.edu.
J R
JR
Moskal
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques
D000928:Antidepressive Agents; C121001:NR2B NMDA receptor; D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; C507283:GLYX-13 peptide
GLYX-13; LTP; NMDA receptor; depression; hippocampus; medial prefrontal cortex