title: The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function.
abstract: Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2C-containing NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition. Specifically, pyramidal neurons in the medial prefrontal cortex (mPFC) of GluN2C knockout mice have reduced mEPSC frequency and dendritic spine density and a contrasting higher frequency of mIPSCs. In addition a greater number of perisomatic GAD67 puncta was observed suggesting a potential increase in parvalbumin interneuron inputs. At a network level the GluN2C knockout mice were found to have a more robust increase in power of oscillations in response to NMDAR blocker MK-801. Furthermore, GluN2C heterozygous and knockout mice exhibited abnormalities in cognition and sensorimotor gating. Our results demonstrate that loss of GluN2C subunit leads to cortical excitatory-inhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders.
authors.affiliation: Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Gupta
authors.affiliation: Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Ravikrishnan
authors.affiliation: Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Jinxu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Nebraska-Medical Center, Omaha, NE, 68198, USA.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Ratnamala
authors.initials: R
authors.lastname: Pavuluri
authors.affiliation: Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Brandon G
authors.initials: BG
authors.lastname: Hillman
authors.affiliation: Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Pauravi J
authors.initials: PJ
authors.lastname: Gandhi
authors.affiliation: Psychology, Creighton University, Omaha, NE 68178, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Stairs
authors.affiliation: Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, R.T.M. Nagpur University, Nagpur, Maharashtra 440033, India.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Ugale
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Nebraska-Medical Center, Omaha, NE, 68198, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Monaghan
authors.affiliation: Department of Pharmacology, Omaha, NE 68178, USA.
authors.forename: Shashank M
authors.initials: SM
authors.lastname: Dravid
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008867:Microtomy; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010622:Phencyclidine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D065808:Prepulse Inhibition / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: D018691:Excitatory Amino Acid Antagonists; C432823:NR2C NMDA receptor; D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010622:Phencyclidine