title: Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity.
abstract: The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC and hippocampus. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2B-containing receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders such as autism.
authors.affiliation: Department of Pharmacology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Gupta
authors.affiliation: Department of Pharmacology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
authors.forename: Roopali
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Department of Pharmacology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
authors.forename: Ratnamala
authors.initials: R
authors.lastname: Pavuluri
authors.affiliation: Neurochemistry Laboratory, Boys Town National Research Hospital, 555 North 30th Street, Omaha, NE 68178, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Morley
authors.affiliation: Department of Psychology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Stairs
authors.affiliation: Department of Pharmacology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA. Electronic address: ShashankDravid@creighton.edu.
authors.forename: Shashank M
authors.initials: SM
authors.lastname: Dravid
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology* / Q000254:growth & development; D049229:Dendritic Spines / Q000502:physiology* / Q000648:ultrastructure; D003891:Desipramine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D005969:Glutamate Dehydrogenase; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000172:deficiency* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D003891:Desipramine; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005969:Glutamate Dehydrogenase; D010636:Phenols; D010880:Piperidines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; C121001:NR2B NMDA receptor; C109643:Ro 25-6981; C570817:GluD1 protein, mouse; C104722:glutamate receptor ionotropic, AMPA 2
keywords: Dendritic spine; GRID1; GluD1; GluN2B; Glutamate