GluN2C/GluN2D subunit‐selective NMDA receptor potentiator CIQ reverses MK‐801‐induced impairment in prepulse inhibition and working memory in Y‐maze test in mice

Abstract

BACKGROUND AND PURPOSEDespite ample evidence supporting the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (D-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). EXPERIMENTAL APPROACHThe effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. KEY RESULTSWe found that systemic administration of CIQ (20 mg·kg , i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801-and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. CONCLUSION AND IMPLICATIONSTogether, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia.

GluN2D N-Methyl-D-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia

“…Together, these results suggest that GluN2D subunits might contribute significantly to the neuronal networks thought to be pivotal in cognitive processing, which are disrupted in schizophrenia. These findings suggest that pharmacologic augmentation of signaling mediated by GluN2D-containing NMDARs may be of therapeutic benefit in schizophrenia, a finding consistent with recent animal studies (Suryavanshi et al, 2014). .…”

d-Cycloserine augmentation of cognitive remediation in schizophrenia

“…DCS also improves auditory discrimination performance in rodents (Thompson and Disterhoft, 1997). Consistent with D-cycloserine’s memory effects being mediated by activity at NR2C-containing NMDARs, CIQ, a more selective potentiator of NR2C/2D-containing NMDARs, enhances retention of fear conditioning and extinction learning in rats and reverses MK801-induced deficits in prepulse inhibition and working memory (Ogden et al, 2013; Suryavanshi et al, 2013). …”

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…Treatments with antipsychotic drugs improve those deficits in rats and humans (Curzon et al 1994;Sanchez-Morla et al 2009;Suryavanshi et al 2014). It is known that patients with FXS are hyperarousal in situations of excessive stimulation and habituate poorly to sensory stimuli (Berry-Kravis 2014).…”