Developmental changes in cerebral NAD and neuroenergetics of an antioxidant compromised mouse model of schizophrenia
Defects in essential metabolic regulation for energy supply, increased oxidative stress promoting excitatory/inhibitory imbalance and phospholipid membrane dysfunction have been implicated in the pathophysiology of schizophrenia (SZ). The knowledge about the developmental trajectory of these key pathophysiological components and their interplay is important to develop new preventive and treatment strategies. However, this assertion is so far limited. To investigate the developmental regulations of these key components, we assessed, for the first time, in vivo redox state from the oxidized (NAD+) and reduced (NADH) form of Nicotinamide Adenine Dinucleotide (NAD), energy and membrane metabolites, neurotransmitters ({gamma}-aminobutyrate and glutamate) by 31P and 1H MRS during the neurodevelopment of a SZ animal model with genetically compromised glutathione synthesis (gclm-KO mice). When compared to age-matched wild type (WT), an increase in NAD+/NADH redox ratio was found in gclm-KO mice until early adulthood, followed by a decrease in full adults as observed in patients. Especially, in early postnatal life (P20, corresponding to childhood), levels of several metabolites were altered in gclm-KO mice, including NAD+, ATP, phosphocreatine, intracellular pH, glutamine + glutamate and membrane phospholipids components, suggesting an interactive compensation for redox dysregulation between NAD, energy metabolism, and neurotransmission. The identified temporal neurometabolic regulations provide insights in preventive treatment targets for at-risk individuals, and other neurodevelopmental disorders involving oxidative stress and energetic dysfunction.