The role of SIRT3 in mediating the cognitive deficits and neuroinflammatory changes associated with a developmental animal model of schizophrenia

Abstract

Abstract The neuroinflammatory state may contribute to the pathogenesis of many mental disorders including schizophrenia. Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for activation of proteins involved in mitochondria quality control, such as Sirtuin3 (SIRT3). Our previous study had found that nicotinamide (NAM) (a precursor of NAD+) administration could rescue Early life stress (ELS)-induced neuroinflammation and down-regulation of SIRT3 in adult offspring. However, it is unclear how SIRT3 is involved in the neuroinflammatory state induced by ELS and whether it is key to the neuroprotective effects of NAM in this animal model of schizophrenia. The present study used 24h maternal separation (MS) as ELS to Wistar rat pups on the postnatal day (PND) 9. At the adult stage, Schizophrenia-like behaviors and memory impairments were detected by behavioral tests. Microglial activation, pro-inflammatory cytokine expression, and NAD+/SIRT3 expression were detected in the prefrontal cortex (PFC) and hippocampus (HIPP). Meanwhile, NAM, and the SIRT3 activator Honokiol (HNK), and the SIRT3 inhibitor 3-TYP were used as an intervention in vivo to explore whether NAD+/SIRT3 axis is involved in the neuroinflammatory state induced by ELS. Our results showed that MS on PND9 could induce schizophrenia-like behaviors and synchronously caused M1 microglial activation, pro-inflammatory cytokine over-expression, NAD+ decline, lower expression of SIRT3, and increased ace-SOD2 expression at the adult stage. NAD+ supplement could block this process and alleviate the pro-inflammatory state in the PFC and HIPP, and normalize the behavioral alterations of the MS animals. Furthermore, administration with HNK for 15 days from PND56 to PND70 could provide neuroprotective effects on the HIPP and PFC of MS rats, as confirmed by cognitive recovery, decreased pro-inflammatory cytokine over-expression, and blunted M1 microglia activation in the MS rats. Meanwhile, 3-TYP administration in the control group and the NAM-treated MS rats caused M1 microglial activation, pro-inflammatory cytokine over-expression, and cognitive deficits. Taken together, the results demonstrated that SIRT3 mediated the stabilizing effect of NAD+ on normalizing M1 microglial activation, neuroinflammation, and behavioral phenotypes in MS rats.