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Program Number: W190      Day / Time: Wednesday, Dec 11, 5:30 PM – 7:30 PM

GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Produces Long Lasting Antidepressant-like Effects through Modulation of Long-term Synaptic Plasticity

Category: Pharmacology: pre-clinical       Sub-Category: ACNP Fellows, Members, Associate Members, and Emeritus
Jeffrey Burgdorf – Northwestern University, Evanston, Illinois
Xiao-lei Zhang – New York Medical College, Valhalla, New York
Amanda Gross – Naurex, Inc, Evanston, Illinois
Roger Kroes – Northwestern University, Evanston, Illinois
Patric Stanton – New York Medical College, Valhalla, New York
J. David Leander – Naurex, Inc, Evanston, Illinois
Ronald M. Burch – Naurex, Inc, Morris, Connecticut
Joseph Moskal – Northwestern University, Evanston, Illinois
J. Burgdorf, Part 1: Naurex ,Inc, Part 2: Naurex ,Inc, Part 3: Naurex ,Inc; X. Zhang, Nothing to Disclose; A. Gross, Part 5: Naurex, Inc; R. Kroes , Part 1: Naurex, Inc, Part 2: Naurex, Inc, Part 4: Naurex, Inc; P. Stanton , Part 1: Naurex, Inc, Part 2: Naurex, Inc, Part 4: Naurex, Inc; J. Leander, Part 1: Naurex, Inc, AgeneBio, Nektar, and CoLucid; R. Burch, Part 5: Naurex, Inc; J. Moskal, Part 1: Naurex, Inc, Part 2: Naurex, Inc, Part 3: Naurex, Inc

Background: GLYX-13, a glycine-site functional partial agonist at the NMDAR, is currently in phase II clinical development as an adjunctive therapy for major depressive disorder (clinicaltrials.gov identifier NCT01684163). GLYX-13 has been shown to: a) preferentially enhance conductance of NR2B-containing NMDARs at rat Schaffer collateral-CA1 synapses in vitro; b) enhance the magnitude of long-term potentiation (LTP) of synaptic transmission while simultaneously reducing that of long-term depression (LTD), which differentiates GLYX-13 from other NMDAR modulators such as D-cycloserine. In animal studies, GLYX-13 has been shown to: a) enhance performance in several hippocampus-dependent learning tasks in both young adult and learning-impaired aged rats;  and d) produce an antidepressant-like effects in a variety of models without ketamine-like dissociative, addictive or sedative side effects.

Methods:
Chronic Unpredictable Stress (CUS) Procedure:  Male Sprague-Dawley (SD) rats (2-3 Months old) received 21 days of CUS: 9 different CUS stressors were used (2 stressors per day). Animals in the CUS groups received a single optimal dose of GLYX-13 (3 mg/kg IV; n = 10) previously shown to produce a robust antidepressant-like response or sterile saline vehicle ( n = 10).  Porsolt Test:  Animals were placed in a 46 cm tall x 20 cm in diameter clear glass tube filled to 30 cm with tap water (23 ± 1 °C) for 15 min on the first day (habituation) and 5 min on the subsequent test days (1 hr, 24 hrs, 1 week, 2 weeks post-dosing).  Sucrose Preference Test:  Rats were exposed to a palatable sucrose solution (1%; Sigma, USA) for 48 hours, followed by 4 hours of water deprivation and a 1 hour exposure to two identical bottles, one filled with sucrose solution and the other with tap water.  Novelty Induced Hypophagia (NIH) Test:  Animals were food deprived on the night before testing, and lab chow was placed into the center chamber of the open field (40 x 40 x20 cm) for 10 min under dim-red lighting. Ultrasonic Vocalization (USV) Test:  Animals received 3 min of heterospecific rough-and-tumble play consisting of alternating 15 s blocks of heterospecific play and 15 s of no-stimulation.  Microarray Analyses:  Triplicate microarray analyses were performed using the medial prefrontal cortex (MPFC) isolated from individual non-CUS treated animals injected with GLYX- 13 (3 mg/kg IV), or saline vehicle (1 ml/kg IV). Individual 45-mer oligonucleotides complementary to sequences of 1178 cloned rat CNS mRNAs were synthesized on a PolyPlex™ 96-well oligonucleotide synthesizer (GeneMachines®, USA) and spotted in triplicate onto epoxy coated slides (Telechem, USA) using an OmniGrid™ robotic microarrayer (GeneMachines®). Hippocampal Slice Electrophysiology:  Hippocampal slices were prepared from adult male SD rats 24 hours after a single injection of GLYX-13 (3 mg/kg IV), ketamine (10 mg/kg IV) or vehicle. LTP at Schaffer collateral-CA1 synapses was measured in response to three submaximal bouts of high-frequency Schaffer collateral stimulation (2x100Hz/800ms). 

Results:
A single IV dose of GLYX-13 produced a long-lasting antidepressant-like effect in the Porsolt, sucrose preference, and NIH tests in rats exposed to CUS.  GLYX-13 also produced a long-lasting antidepressant-like effect in the USVs test and increased positive emotional learning in rats exposed to CUS. The AMPA / kainate receptor antagonist NBQX, 24 hrs post-dosing, occluded the antidepressant-like effect of GLYX-13 in the Porsolt test.  GLYX-13, 24 hrs and 2 weeks post-dosing, showed enrichment in LTP- and LTD-associated genes in the medial prefrontal cortex as measured by microarray.  GLYX-13 metaplasticly enhances LTP 24 h and 1 week following a single dose, and persistently enhances LTP following multiple bi-weekly doses.

Conclusions:
We have hypothesized that the long-lasting antidepressant effects of GLYX-13 are due to metaplastic enhancement in long-term activity-dependent synaptic plasticity.  Based on the results reported here we suggest that the long-lasting antidepressant-like effects of GLYX-13 are due at least in part to metaplasticity mechanisms associated with NMDAR-triggered induction of LTP.  The induction/upregulation of LTD-associated transcripts at 1 hr by GLYX-13 may produce a shift in the threshold for future synaptic plasticity processes.  This shift may initially favor LTD and be associated with a more sustained rebound that persistently favors future LTP since it is well established that the thresholds for LTD and LTP are plastic. 

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