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Review
. 2022 Sep 15;92(6):460-469.
doi: 10.1016/j.biopsych.2022.04.004. Epub 2022 Apr 21.

Impact of Maternal Immune Activation on Nonhuman Primate Prefrontal Cortex Development: Insights for Schizophrenia

Kari L Hanson  1 , Simone E Grant  2 , Lucy H Funk  2 , Cynthia M Schumann  3 , Melissa D Bauman  4
Affiliations
Review

Impact of Maternal Immune Activation on Nonhuman Primate Prefrontal Cortex Development: Insights for Schizophrenia

Kari L Hanson et al. Biol Psychiatry. .

Abstract

Late adolescence is a period of dynamic change in the brain as humans learn to navigate increasingly complex environments. In particular, prefrontal cortical (PFC) regions undergo extensive remodeling as the brain is fine-tuned to orchestrate cognitive control over attention, reasoning, and emotions. Late adolescence also presents a uniquely vulnerable period as neurodevelopmental illnesses, such as schizophrenia, become evident and worsen into young adulthood. Challenges in early development, including prenatal exposure to infection, may set the stage for a cascade of maladaptive events that ultimately result in aberrant PFC connectivity and function before symptoms emerge. A growing body of research suggests that activation of the mother's immune system during pregnancy may act as a disease primer, in combination with other environmental and genetic factors, contributing to an increased risk of neurodevelopmental disorders, including schizophrenia. Animal models provide an invaluable opportunity to examine the course of brain and behavioral changes in offspring exposed to maternal immune activation (MIA). Although the vast majority of MIA research has been carried out in rodents, here we highlight the translational utility of the nonhuman primate (NHP) as a model species more closely related to humans in PFC structure and function. In this review, we consider the protracted period of brain and behavioral maturation in the NHP, describe emerging findings from MIA NHP offspring in the context of rodent preclinical models, and lastly explore the translational relevance of the NHP MIA model to expand understanding of the etiology and developmental course of PFC pathology in schizophrenia.

Keywords: Animal models; Macaque; Neurodevelopmental disorders; Neuroimmunology; Poly IC; Rhesus monkey.

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Conflict of interest statement

The authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Organization of the PFC in the human, macaque, and rat brain. Expansion and elaboration of PFC regions has been a hallmark of primate evolution, including territories involved in executive function, such as BAs 9 and 46 of the dlPFC, language and speech production (BA 44/45), and socio-emotional processing (BAs 47/12, 10, 11, and 13). Granular cortices, defined by the presence of a clear layer IV, represent canonical PFC territories with unique functional architectonics that subserve complex multimodal processing. Agranular territories more closely resemble the ventromedial PFC and aCC (BAs 24 and 32) of the primate brain and serve as a critical interface for integration of limbic and sensory information. aCC, anterior cingulate cortex; BA, Brodmann area; dlPFC, dorsolateral prefrontal cortex; dmPFC, dorsomedial PFC; FEF, frontal eye fields; M1, primary motor area; M2, supplementary motor area; mPFC, medial PFC; OFC, orbitofrontal cortex; vlPFC, ventrolateral PFC. [Macaque and rodent illustrations were adapted with permission from Preuss and Wise (17).]
Figure 2.
Figure 2.
Evidence of PFC dysfunction in schizophrenia populations and preclinical MIA models. A rapidly growing literature from rodent MIA models paired with decades of human schizophrenia studies highlights changes in PFC-related behavior and underlying neurobiology in the animal model and the clinical population. Although the NHP MIA model literature is less extensive compared with the rodent MIA literature owing to the time and resources required to generate each cohort, emerging findings from NHP MIA offspring also include changes in social and cognitive development, reductions in frontal gray and white matter, altered dorsolateral PFC dendritic morphology, and gene expression. MIA, maternal immune activation; NHP, nonhuman primate; PFC, prefrontal cortex.
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