Nicotinamide Reverses Deficits in Puberty-born Neurons and Cognitive Function after Maternal Separation

Background: Neuronal loss is one of the important pathological features of schizophrenia. Early life stress (ELS) is associated with the development of schizophrenia. The hippocampus undergoes significant development during childhood and is extremely reactive to stress. In rodent models, ELS can induce neuroinflammation and hippocampal neuronal loss, and a schizophrenia-like behavioral phenotype. Nicotinamide (NAM) administration is found to inhibit microglial inflammation. Whether treatment with NAM during adolescence can reduce hippocampal neuronal loss and abnormal behaviors induced by ELS is unknown. Methods: : The present study used 24h maternal separation (MS) as ELS to Wistar rat pups on postnatal day (PND) 9. On PND 35 animals were given a single intraperitoneal injection of BrdU to label dividing neurons, and gaved with NAM from PND35 to PND65. Schizophrenia-like behavior tests were performed. Western blot and immunofluorescence staining detected the NAD+/Sirt3/SOD2 pathway-related proteins. Results: : Compared with the control group, only at the adult stage (PND56-65) but not the adolescent stage (PND31-40), animals of the MS group exhibited pre-pulse inhibition (PPI) deficits and cognitive impairment that mimic symptoms of schizophrenia. The survival and activity of puberty-born neurons, the expression of nicotinamide adenine dinucleotide (NAD+) and Sirtuin3 (Sirt3) in the hippocampus were decreased in the MS group rats at adulthood stage, followed by acetylated superoxide dismutase 2 (SOD2) increase, and microglial activation, and a significant increase of IL-1β, TNF-α, IL-6 expression. All the effects of MS at PND9 could be reversed by NAM administration at the adolescent stage (PND 35-65). Conclusions: : The results demonstrated that MS may lead to schizophrenia-like phenotypes and lasting effects on the hippocampus, and highlight the utility of NAM during adolescence for restoring normal hippocampal function, ameliorating schizophrenia-like behavior.