Studying Astrocytes’ Role in Potential Harmful Effects of Maternal Immune Activation

By Dirk Hoffman

Led by Mikhail V. Pletnikov, MD, PhD, professor and chair of physiology and biophysics in the Jacobs School of Medicine and Biomedical Sciences, the researchers were awarded a five-year, $3.75 grant from the National Institute of Mental Health titled “Dissecting the Role for Astrocytes in Mediating Adverse Outcomes of Maternal Immune Activation.”

Pletnikov is the contact principal investigator on the multiple principle investigators (MPI) grant with Samir Haj-Dahmane, PhD, professor of pharmacology and toxicology in the Jacobs School; and Atsushi Kamiya, MD, PhD, professor of psychiatry and behavioral sciences at Johns Hopkins University.

“This MPI grant is a great example of team science,” Pletnikov says. “It features inter-departmental collaboration at the Jacobs School, synergy with Roswell Park Comprehensive Cancer Care, as well as inter-university collaboration with Johns Hopkins University.”

Despite the growing appreciation of the significance of non-neuronal brain cells in healthy and diseased brains during development and adulthood, the role of astrocytes in neurodevelopmental abnormalities remains poorly understood, Pletnikov notes.

To address this major knowledge gap, the researchers conducted pilot studies that suggest that maternal immune activation (MIA) increases impulsivity-like behaviors and amphetamine-induced hyperactivity and enhances extracellular levels of glutamate and dopamine in the dorsal striatum (DS).

Additionally, they found that MIA also increased pro-inflammatory signatures of astrocytes, including up-regulation of the Nuclear Factor kappa B pathway and increased glial fibrillary acidic protein immunoreactivity in DS astrocytes. 

“Our research is the first systematic evaluation of changes in astrocyte functions in offspring exposed to prenatal viral infection,” he adds. “We think that our research can help identify new astrocyte-associated targets for treatment of the human conditions.”

This team science project will use cutting-edge methods of in vivo imaging, ex vivo and in vivo electrophysiology, single-cell RNA sequence, modern bioinformatics approaches, and genetic technologies.  

The RNAseq preliminary data were generated with the assistance of Urs Meyer, PhD, a professor in the Institute of Pharmacology and Toxicology at the University of Zurich – Vetsuisse in Switzerland.

The study’s specific aims are:

• to characterize the neurobehavioral, neurochemical, and physiological alterations in astrocytes in offspring exposed in utero to an immune stimulator that mimics viral infections
• to determine the mechanisms whereby dysfunctional astrocytes affect synaptic neurotransmission in the basal ganglia to produce excessive release of dopamine, leading to hyperactivity in the offspring in adulthood
• to identity transcriptional changes in astrocytes and microglia, critical brain cells that interact with astrocytes, to guide efforts to develop rescue treatments using genetic manipulation and pharmacological interventions

Co-investigators from the Jacobs School are:

• Kateryna (Kate) Murlanova, PhD, research scientist and research assistant professor of physiology and biophysics
• Roh-Yu Shen, PhD, professor of pharmacology and toxicology

Other co-investigators are:

• Dwight Bergles, PhD, professor of neuroscience at Johns Hopkins University
• Henry Withers, PhD, research assistant professor of oncology in the Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center