The NMDA receptor GluN2C subunit controls cortical excitatoryinhibitory balance, neuronal oscillations and cognitive function

Authors

Subhash C. Gupta, University of Nebraska-Medical Center
Aparna Ravikrishnan, University of Nebraska-Medical Center
Jinxu Liu, University of Nebraska-Medical Center
Zhihao Mao, University of Nebraska-Medical Center
Ratnamala Pavuluri, University of Nebraska-Medical Center
Brandon G. Hillman, University of Nebraska-Medical Center
Pauravi J. Gandhi, University of Nebraska-Medical Center
Dustin J. Stairs, Creighton University
Ming Li, University of Nebraska-Lincoln
Rajesh R. Ugale, R.T.M. Nagpur University
Daniel T. Monaghan, University of Nebraska-Medical Center
Shashank M. Dravid, University of Nebraska-Medical CenterFollow

Date of this Version

12-6-2016

Citation

The Author(s) 2016

Comments

6:38321 | DOI: 10.1038/srep38321

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 GluN2Ccontaining 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 excitatoryinhibitory imbalance and abnormal neuronal oscillations associated with neurodevelopmental disorders.