Dysregulation of the glutamatergic system and its receptors in medial prefrontal cortex (mPFC) has been implicated in major depressive disorder. Recent preclinical studies have shown that enhancing NMDA receptor (NMDAR) activity can exert rapid antidepressant-like effects. AGN-241751, an NMDAR positive allosteric modulator (PAM), is currently being tested as an antidepressant in clinical trials, but the mechanism and NMDAR subunit(s) mediating its antidepressant-like effects are unknown. We therefore used molecular, biochemical, and electrophysiological approaches to examine the cell-type-specific role of GluN2B-containing NMDAR in mediating antidepressant-like behavioral effects of AGN-241751. We demonstrate that AGN-241751 exerts antidepressant-like effects and reverses behavioral deficits induced by chronic unpredictable stress in mice. AGN-241751 treatment enhances NMDAR activity of excitatory and parvalbumin-inhibitory neurons in mPFC, activates Akt/mTOR signaling, and increases levels of synaptic proteins crucial for synaptic plasticity in the prefrontal cortex. Furthermore, cell-type-specific knockdown of GluN2B-containing NMDARs in mPFC demonstrates that GluN2B subunits on excitatory, but not inhibitory, neurons are necessary for antidepressant-like effects of AGN-241751. Together, these results demonstrate antidepressant-like actions of the NMDAR PAM AGN-241751 and identify GluN2B on excitatory neurons of mPFC as initial cellular trigger underlying these behavioral effects.
Subscribe to Journal
Get full journal access for 1 year
only $38.38 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–858.
Lépine JP, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):3–7.
Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649–59.
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.
Curtin SC, Warner M, Hedegaard H. Increase in suicide in the United States, 1999–2014. NCHS Data Brief. 2016;241:1–8.
Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G, et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry. 2002;7(Suppl 1):S71–80. https://doi.org/10.1038/sj.mp.4001021.
Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry. 2013;73:1133–41.
Duman RS, Shinohara R, Fogaça MV, Hare B. Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function. Mol Psychiatry. 2019;24:1816–32.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.
Moghaddam B, Krystal JH. Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull. 2012;38:942–9.
Morgan CJA, Curran HV. Ketamine use: a review. Addiction 2012;107:27–38.
Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013;38:729–42.
Burch R, Preskorn S, Bastin L, Yu W, Burgdorf J, Moskal J. Adjunctive GLYX-13 induces prolonged efficacy in subjects with major depressive disorder (MDD). Neuropsychopharmacology. 2014;39:S335.
Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, et al. Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects. Int J Neuropsychopharmacol. 2019;22:247–59.
Huang CC, Wei IH, Huang CL, Chen KT, Tsai MH, Tsai P, et al. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry. 2013;74:734–41.
Chen KT, Tsai MH, Wu CH, Jou MJ, Wei IH, Huang CC. AMPA receptor-mTOR activation is required for the antidepressant-like effects of sarcosine during the forced swim test in rats: insertion of AMPA receptor may play a role. Front Behav Neurosci. 2015;9:162.
Malkesman O, Austin DR, Tragon T, Wang G, Rompala G, Hamidi AB, et al. Acute d-serine treatment produces antidepressant-like effects in rodents. Int J Neuropsychopharmacol. 2012;15:1135–48.
Banerjee P, Donello J, Li YX, Bertelsen K, Gu Y-X, Zhang X-L, et al. AGN-241751, an orally bioavailable positive NMDA receptor modulator, exhibits rapid and sustained antidepressant-like effects in rodents. Biol Psychiatry. 2019;85:S348.
Chan SY, Matthews E, Burnet PW. On or off?: modulating the N-methyl-D-aspartate receptor in major depression. Front Mol Neurosci. 2017;9:169.
Papadia S, Hardingham GE. The dichotomy of NMDA receptor signaling. Neuroscientist. 2007;13:572–9.
Tasic B, Menon V, Nguyen TN, Kim TK, Jarsky T, Yao Z, et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci. 2016;19:335–46.
Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J Clin Invest. 2020;130:1336–49.
Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Natl Acad Sci. 2015;112:8106–11.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.
Schmidt HD, Duman RS. Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology. 2010;35:2378–91.
Iwata M, Ota KT, Li XY, Sakaue F, Li N, Dutheil S, et al. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol Psychiatry. 2015;80:12–22.
Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Alreja M, et al. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Invest. 2016;126:2482–94.
Isingrini E, Camus V, Le Guisquet AM, Pingaud M, Devers S, Belzung C. Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice. PLoS ONE. 2010;5:e10404.
Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985;14:149–67.
Kato T, Duman RS. Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: convergent mechanisms. Pharm Biochem Behav. 2020;188:172827.
Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology. 2005;52:90–110.
Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife. 2014;3:e03581. https://doi.org/10.7554/eLife.03581.
Miller OH, Bruns A, Ben Ammar I, Mueggler T, Hall BJ. Synaptic regulation of a thalamocortical circuit controls depression-related behavior. Cell Rep. 2017;20:1867–80.
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61.
Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol. 2008;28:631–7.
Pothula S, Kato T, Liu RJ, Wu M, Gerhard D, Shinohara R, et al. Cell-type specific modulation of NMDA receptors triggers antidepressant actions. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-0796-3.
Wilkinson ST, Sanacora G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today. 2019;24:606–15.
Hunt DL, Castillo PE. Synaptic plasticity of NMDA receptors: mechanisms and functional implications. Curr Opin Neurobiol. 2012;22:496–508.
Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996;29:23–6.
Radley JJ, Morrison JH. Repeated stress and structural plasticity in the brain. Ageing Res Rev. 2005;4:271–87.
Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20.
Goldwater DS, Pavlides C, Hunter RG, Bloss EB, Hof PR, McEwen BS, et al. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience. 2009;164:798–808.
Gourley SL, Kedves AT, Olausson P, Taylor JR. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology. 2009;34:707–16.
Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 2012;73:962–77.
Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:70–5.
Nowak G, Ordway GA, Paul IA. Alterations in the N-methyl-d-asparatate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res. 1995;675:157–64.
Khan MA, Houck DR, Gross AL, Zhang XL, Cearley C, Madsen TM, et al. NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-β-Lactam That Modulates Synaptic Plasticity Processes Associated with Learning and Memory. Int J Neuropsychopharmacol. 2018;21:242–54.
Widman AJ, McMahon LL. Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci USA. 2018;115:E3007–16.
Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology. 2017;42:1231–42.
Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun. 2019;10:223.
Berry A, Bellisario V, Capoccia S, Tirassa P, Calza A, Alleva E, et al. Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviors and leads to reduced brain BDNF levels in C57BL/6J mice. Psychoneuroendocrinology. 2012;37:762–72.
Ieraci A, Mallei A, Popoli M. Social isolation stress induces anxious-depressive-like behavior and alterations of neuroplasticity-related genes in adult male mice. Neural Plast. 2016;2016:6212983.
Mumtaz F, Khan MI, Zubair M, Dehpour AR. Neurobiology and consequences of social isolation stress in animal model-A comprehensive review. Biomed Pharmacother. 2018;105:1205–22.
We thank Xiao Yuan Li for her help with genotyping of mouse lines.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Pothula, S., Liu, RJ., Wu, M. et al. Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00882-7