Mitochondria play an essential role in the trajectory of adolescent neurodevelopment and behavior in adulthood: evidence from a schizophrenia rat model

Ample evidence implicate mitochondria in early brain development. However, to the best of our knowledge, there is only circumstantial data for mitochondria involvement in late brain development occurring through adolescence, a critical period in the pathogenesis of various psychiatric disorders, specifically schizophrenia. In schizophrenia, neurodevelopmental abnormalities and mitochondrial dysfunction has been repeatedly reported. Here we show a causal link between mitochondrial transplantation in adolescence and brain functioning in adulthood. We show that transplantation of allogenic healthy mitochondria into the medial prefrontal cortex of adolescent rats was beneficial in a rat model of schizophrenia, while detrimental in healthy control rats. Specifically, disparate initial changes in mitochondrial function and inflammatory response were associated with opposite long-lasting changes in proteome, neurotransmitter turnover, neuronal sprouting and behavior in adulthood. A similar inverse shift in mitochondrial function was also observed in human lymphoblastoid cells deived from schizophrenia patients and healthy subjects due to the interference of the transplanted mitochondria with their intrinsic mitochondrial state. This study provides fundamental insights into the essential role of adolescent mitochondrial homeostasis in the development of normal functioning adult brain. In addition, it supports a therapeutic potential for mitochondria manipulation in adolescence in disorders with neurodevelopmental and bioenergetic deficits, such as schizophrenia, yet emphasizes the need to monitor individuals’ state including their mitochondrial function and immune response, prior to intervention.