Abstract
Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice.Methods: The effect of GLYX-13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry.Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown.Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13.
Highlights
Schizophrenia, a chronic and degenerative disease, has an overall lifetime risk of 1%
We found that N-Methyl D-aspartate receptor subtype 2B (NR2B) knockdown produced memory and Prepulse inhibition (PPI) deficits without any changes in locomotor activity
Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and disrupted-in-schizophrenia 1 (DISC1) in the hippocampus may account for the molecular mechanisms of GLYX-13
Summary
Schizophrenia, a chronic and degenerative disease, has an overall lifetime risk of 1%. Recent studies have suggested that N-methylD-aspartate receptor (NMDAR) hypofunction contributes to the negative symptoms and cognitive impairments observed in schizophrenia (Gilmour et al, 2012; Jadi et al, 2016; Dauvermann et al, 2017). This putatively occurs due to dysfunction of glutamate transmission at NMDARs in this disease. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects It remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice
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