# Maternal Immune Activation Leads to Mitochondrial Dysfunction and a Social Deficit in Offspring That Is Reversed by Nicotinamide Riboside

## TL;DR

Maternal immune activation during pregnancy causes mitochondrial problems and social deficits in offspring, which can be reversed with a supplement called nicotinamide riboside.

## Contribution

This study shows that mitochondrial dysfunction caused by maternal immune activation can be reversed using nicotinamide riboside.

## Key findings

- Maternal immune activation impairs mitochondrial membrane potential in offspring from juvenile to adult stages.
- MIA alters gene expression related to mitochondrial energy production in the medial prefrontal cortex.
- Nicotinamide riboside reduces social interaction deficits caused by maternal immune activation.

## Abstract

Background: Maternal immune activation (MIA) during pregnancy is a known risk factor for several neurodevelopmental and psychiatric disorders, including schizophrenia. In rodent models, MIA is commonly induced using polyinosinic/polycytidylic acid (Poly(I/C)), a viral mimetic that activates Toll-like receptor 3 (TLR3) signaling and elicits an inflammatory response in both the dam and the fetuses. MIA results in various behavioral abnormalities in offspring, including deficits in social interaction. Recent studies have shown that MIA decreases the ability to maintain mitochondrial membrane potential (ΔΨm), the electrical component of the electrochemical gradient required for ATP production and alters mitochondrial protein expression in brain tissue isolated from adult offspring. Methods: In the present study, we monitor ΔΨm non-invasively in vivo using a previously published bioluminescence probe in juvenile and adult MIA offspring. We then investigated gene expression in the medial prefrontal cortex of MIA offspring by analyzing a previously published RNA sequencing dataset in combination with MitoCarta3.0, a comprehensive inventory of genes involved in mitochondrial function. Finally, we tested the hypothesis that this mitochondrial dysfunction contributes to the behavioral deficits observed in MIA offspring. Results: We have observed impaired ΔΨm maintenance in juvenile MIA offspring that persists into adulthood. Also, we found that MIA alters the expression of many genes associated with mitochondrial energy production. We demonstrated that nicotinamide riboside, a precursor to NAD+ known to restore ΔΨm, significantly attenuates MIA-induced social interaction deficits. Conclusions: Together, these findings highlight mitochondrial function as a promising therapeutic target for symptoms associated with schizophrenia and support the potential for drug discovery aimed at enhancing mitochondrial health.