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Increased Striatal Presynaptic Dopamine in a Nonhuman Primate Model of Maternal Immune Activation: A Longitudinal Neurodevelopmental PET Study with Implications for Schizophrenia

Published:November 15, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.10.012

      Abstract

      Background

      Epidemiologic studies suggest maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest MIA is associated with dopaminergic hyperfunction in young adult offspring.

      Methods

      In this unique, prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine ([18F]FMT) PET to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n=13) injected with a modified form of the inflammatory viral mimic, Polyinosinic:polycytidylic acid, in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine was compared to control offspring born to dams that received saline (n=10) or no injection (n=4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work from this cohort found decreased prefrontal gray matter volume in MIA offspring vs. controls between 6-45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized a delayed (relative to the gray matter decrease) increase in striatal FMT signal in the MIA group vs. controls.

      Results

      [18F]FMT signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months.

      Conclusions

      These findings are highly relevant for the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

      Keywords

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