title: NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism.
abstract: Drugs targeting the glutamate N-methyl-d-aspartate receptor (NMDAR) may be efficacious for treating mood disorders, as exemplified by the rapid antidepressant effects produced by single administration of the NMDAR antagonist ketamine. Though the precise mechanisms underlying the antidepressant-related effects of NMDAR antagonism remain unclear, recent studies implicate specific NMDAR subunits, including GluN2A and GluN2B, as well as the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor interacting molecule, PSD-95. Here, integrating mutant and pharmacological in mice, we investigated the contribution of these subunits and molecules to antidepressant-related behaviors and the antidepressant-related effects of the GluN2B blocker, Ro 25-6981. We found that global deletion of GluA1 or PSD-95 reduced forced swim test (FST) immobility, mimicking the antidepressant-related effect produced by systemically administered Ro 25-6981 in C57BL/6J mice. Moreover, the FST antidepressant-like effects of systemic Ro 25-6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but were absent in mutants constitutively lacking GluN2A or PSD-95. Next, we found that microinfusing Ro 25-6981 into the medial prefrontal cortex (mPFC), but not basolateral amygdala, of C57BL/6J mice was sufficient to produce an antidepressant-like effect. Together, these findings extend and refine current understanding of the mechanisms mediating antidepressant-like effects produced by NMDAR-GluN2B antagonists, and may inform the development of a novel class of medications for treating depression that target the GluN2B subtype of NMDAR.
authors: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors: Carly
authors: C
authors: Kiselycznyk
authors: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. Electronic address: nickjury@hotmail.com.
authors: Nicholas J
authors: NJ
authors: Jury
authors: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors: Lindsay R
authors: LR
authors: Halladay
authors: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Kazu
authors: K
authors: Nakazawa
authors: Brain Science Laboratory, The Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors: Masayoshi
authors: M
authors: Mishina
authors: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Heidelberg, Germany.
authors: Rolf
authors: R
authors: Sprengel
authors: Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors: Seth G N
authors: SG
authors: Grant
authors: Laboratory of Translational Neuropharmacology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Per
authors: P
authors: Svenningsson
authors: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors: Andrew
authors: A
authors: Holmes
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists; D051528:Guanylate Kinases; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010636:Phenols; D010880:Piperidines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C501447:Dlg4 protein, mouse; C121673:Gprin1 protein, mouse; C121001:NR2B NMDA receptor; C109643:Ro 25-6981
keywords: Depression; GluA1; GluN2B; Glutamate; PSD-95; Prefrontal cortex