Emerging evidence suggests that mitochondria play a central role in mental health disorders including schizophrenia. Here we investigated whether nicotinamide (NAM) normalized cognitive impairment via a mechanism involving the mitochondrial Sirtuin 3 (SIRT3) pathway. The 24 h maternal separation (MS) rat model was used to mimic schizophrenia-associate phenotypes. Schizophrenia-like behaviors and memory impairments were detected using the pre-pulse inhibition test, novel object recognition test, and Barnes maze test, and neuronal apoptosis was characterized using multiple assays. SIRT3 activity was inhibited pharmacologically or by knockdown in HT22 cells, and BV2 microglia and SIRT3-knockdown HT22 cells were co-cultured in vitro. Mitochondrial molecules were measured by western blotting, and mitochondrial damage was measured with reactive oxygen species and mitochondrial membrane potential assays. Proinflammatory cytokines were assayed by ELISA and microglial activation was detected by immunofluorescence. MS animals showed behavioral and cognitive impairment and increased neuronal apoptosis. Supplementation with NAM or administration of honokiol, a SIRT3 activator, reversed all of the changes in behavioral and neuronal phenotypes. Administration of the SIRT3 inhibitor 3-TYP in control and NAM-treated MS rats caused behavioral and neuronal phenotypes similar to MS. In vitro, inhibition of SIRT3 activity with 3-TYP or by knockdown in HT22 cells increased ROS accumulation and caused neuronal apoptosis in a single-culture system. In co-culture systems, SIRT3 knockdown in HT22 cells activated BV2 microglia and increased levels of TNF-α, IL-6, and IL-1β. The administration of NAM blocked these alterations. Taken together, these data suggest that NAM can rescue neuronal apoptosis and microglial over-activation through the nicotinamide adenine dinucleotide (NAD+)-SIRT3-SOD2 signaling pathway, furthering our understanding of the pathogenesis of schizophrenia and providing avenues for novel treatments.
© 2023. The Author(s).