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

Subhash C. Gupta, Aparna Ravikrishnan, Jinxu Liu, Zhihao Mao, Ratnamala Pavuluri, Brandon G. Hillman, Pauravi J. Gandhi, Dustin Stairs, Ming Li, Rajesh R. Ugale, Daniel T. Monaghan, Shashank M. Dravid

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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.

Original languageEnglish (US)
Article number38321
JournalScientific Reports
Volume6
DOIs
StatePublished - Dec 6 2016

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N-Methyl-D-Aspartate Receptors
Knockout Mice
Cognition
Sensory Gating
Parvalbumins
Dendritic Spines
Dizocilpine Maleate
Pyramidal Cells
Interneurons
Prefrontal Cortex
Schizophrenia
Brain

All Science Journal Classification (ASJC) codes

  • General

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The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function. / Gupta, Subhash C.; Ravikrishnan, Aparna; Liu, Jinxu; Mao, Zhihao; Pavuluri, Ratnamala; Hillman, Brandon G.; Gandhi, Pauravi J.; Stairs, Dustin; Li, Ming; Ugale, Rajesh R.; Monaghan, Daniel T.; Dravid, Shashank M.

In: Scientific Reports, Vol. 6, 38321, 06.12.2016.

Research output: Contribution to journalArticle

Gupta, SC, Ravikrishnan, A, Liu, J, Mao, Z, Pavuluri, R, Hillman, BG, Gandhi, PJ, Stairs, D, Li, M, Ugale, RR, Monaghan, DT & Dravid, SM 2016, 'The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function', Scientific Reports, vol. 6, 38321. https://doi.org/10.1038/srep38321
Gupta, Subhash C. ; Ravikrishnan, Aparna ; Liu, Jinxu ; Mao, Zhihao ; Pavuluri, Ratnamala ; Hillman, Brandon G. ; Gandhi, Pauravi J. ; Stairs, Dustin ; Li, Ming ; Ugale, Rajesh R. ; Monaghan, Daniel T. ; Dravid, Shashank M. / The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function. In: Scientific Reports. 2016 ; Vol. 6.
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