Resilience effect of D3 nutraceutical on NMDA receptor hypofunction theory and dysregulated alpha7 nicotinic acetylcholine receptor function in schizophrenia

Vitamin D3 (VD) deficiency is a global health concern, and its supplementation has been shown to alleviate inflammation and oxidative stress across numerous neurological disorders. However, the beneficial effect of this common nutraceutical in schizophrenia (SCZ) remains inadequately explored. The present study investigated the presupplementation effects of VD on positive and cognitive symptoms in a MK-801induced mouse model of SCZ. MK-801, a non-competitive NMDA receptor antagonist, is a widely used drug that mimics some of the psychotic symptoms associated with SCZ. The repeated administration of a single dose of MK-801 (0.5mg/kg; intraperitoneally) for two weeks produced hyperlocomotion, anxiety- like behavior, and working memory deficits in MK-801-induced SCZ-like mice. These behavioral abnormalities were significantly attenuated in VS5 mice (SCZ mice presupplemented with 500 IU/kg/day of VD). At the molecular level, VD rescued gene expression of major NMDA receptor subunits (NR1, NR2A, NR2B), 7 nicotinic acetylcholine receptors (7nAChRs), and neurotrophin factors (NGF and BDNF). A restoration of PSD-95 protein expression, accompanied by downregulation of calcineurin, was also observed in the prefrontal cortex (PFC) of VS5 mice, suggesting protective effects of VD on synaptic communication and function in SCZ. In vitro studies showed that calcitriol (1 M) treatment of HEK-293 T cells transfected with 7nAChRs potentiated the single-channel current amplitude and demonstrated a direct modulatory effect of this nutraceutical on 7nAChRs expression and function. In silico JASPAR analysis further identified putative Vitamin D response elements (VDREs) within the promoter regions of various target genes, supporting the genomic action of VD. Additionally, VD deficiency was observed in Indian SCZ patients, highlighting its potential clinical relevance. Together with our previous findings (Manjari et al., 2022, 2023), the present study also demonstrates anti-inflammatory, anti-cholinesterase, neurotrophic, and synaptic-enhancing effects of VD, deepening our understanding of the multifaceted neuroprotective effects of the "D3" neurosteroid in neuropsychiatric disorders such as SCZ. HighlightsO_LIVD presupplementation improves the behavioral deficits in MK-801 induced SCZ mice. C_LIO_LINutraceutical intervention normalizes the gene expression of major NMDARs subunits namely, NR1, NR2A, NR2B, in the PFC of SCZ mice. C_LIO_LIVD mediates a restoration in the expression and function of 7nAChRs in SCZ mice. C_LIO_LIVD exhibits neuroprotective, neurotrophic, synaptoprotective, anti-inflammatory and anti-acetylcholinesterase effects, highlighting its therapeutic potential in SCZ. C_LI