Abstract
Introduction
Functional deficit in NMDA‐receptors on parvalbumin (PV)‐positive interneurons (PV‐NMDARs) is central to the pathophysiology of schizophrenia. NMDA channel blockers like ketamine and MK‐801 have shown to produce psychosis by inhibiting GluN2C and GluN2D subunits with greater affinity than other subunits. Recent neuroanatomical and electrophysiological studies have reported expression of GluN2D subunit in PV positive interneurons in corticolimbic regions but the precise distribution of GluN2C subunit especially in PV interneurons remains unknown.
Hence, the objective of the study was to identify the expression pattern of GluN2C subunit in neuronal and non‐neuronal cell population and to perform a side‐by‐side comparison of the effect of partial and complete ablation of GluN2C and GluN2D subunit on pure C57BL/6N mouse strain.
Methods and Results
Immunohistochemistry was used to determine the heterogenous expression of GluN2C using a novel eGFP reporter mouse model. We found the expression of EGFP (GluN2C) with PV positive neurons in nucleus reticularis of the thalamus, globus pallidus externa and interna, ventral pallidum and substantia nigra. Interestingly, EGFP (GluN2C) showed co‐localization with astrocytic marker in the striatum, cortex, hippocampus and amygdala but not with PV positive neurons. GluN2C was found to be enriched in several thalamic relay nuclei including first order and higher order nuclei. GluN2D knockout mouse exhibited hypo‐locomotion and anxiety‐like behavior in the open field test. We found a significant increase in startle amplitude in GluN2C HET but not GluN2C KO and no change in prepulse inhibition (PPI) in either genotype was observed. Increase in startle response was found for GluN2D heterozygous and GluN2D knockout along with lower prepulse inhibition at some decibels. We also found CIQ, a selective positive allosteric modulator for GluN2C/GluN2D subunit, reversed the MK801 induced impairment in PPI in GluN2C wildtype and heterozygous mice but not in GluN2C KO mice. Furthermore, we observed that GluN2C knockout mice but not GluN2D knockout mice were less sensitive to phencyclidine‐induced hyperlocomotion, a model of psychosis. The cell‐type specific expression of both GluN2C and GluN2D subunit may provide more insights into schizophrenia‐like behaviors. Hence, we will confirm psychotic and sensorimotor deficits by selectively deleting GluN2D subunit from PV‐positive interneurons and GluN2C subunit from astrocytes using Cre‐lox strategy.
Conclusion
Together, these results identify the unique expression pattern of GluN2C subunit in neuronal and non‐neuronal cell population. It also demonstrates the preferential involvement of GluN2C‐ containing receptors in phencyclidine‐induced hyperlocomotion and that facilitation of GluN2C subunit may reverse the schizophrenic phenotypes.
Support or Funding Information
R21 NS104705
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.