The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function

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 subun...

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Bibliographic Details
Published in:Scientific reports 2016-12, Vol.6 (1), p.38321-38321, Article 38321
Main Authors: Gupta, Subhash C., Ravikrishnan, Aparna, Liu, Jinxu, Mao, Zhihao, Pavuluri, Ratnamala, Hillman, Brandon G., Gandhi, Pauravi J., Stairs, Dustin J., Li, Ming, Ugale, Rajesh R., Monaghan, Daniel T., Dravid, Shashank M.
Format: Article
Language:English
Subjects:
14
14/19
631/378/2586
631/378/340
Channel gating
Cognitive ability
Dendritic spines
Dizocilpine
Glutamic acid receptors (ionotropic)
Humanities and Social Sciences
Mental disorders
multidisciplinary
N-Methyl-D-aspartic acid receptors
Neurodevelopmental disorders
Oscillations
Parvalbumin
Prefrontal cortex
Pyramidal cells
Rodents
Schizophrenia
Science
Sensorimotor gating
Spine
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep38321