UC Davis MIND Institute researchers have shown in a mouse model that an elevated maternal immune response changes the epigenetic landscape in offspring’s microglia, immune cells found in the brain and spinal cord. These changes affect genes associated with immune signaling and neural development, some of which have been implicated in autism spectrum disorder (ASD). The study was published online in the journal Glia.
“The genes we identified that had differences in methylation and changes in expression showed an overlap or enrichment for genes that had been identified as genetic risk factors for autism, as well as genes that were differentially expressed in autism human brain samples,” said Annie Vogel Ciernia, Autism Research Training Program (ARTP) fellow, senior postdoctoral researcher in the LaSalle lab at UC Davis and first author on the paper.
Epidemiological studies have shown that women who experience asthma, infections and other immune reactions during pregnancy have children who are at higher risk for ASD. However, the science has been murky on how these maternal immune responses translate into neurodevelopmental disorders.
“We wanted to identify some of the mechanisms underlying the epidemiology findings that maternal allergic asthma increases the risk of having a child with ASD,” Vogel Ciernia said.
Epigenetic processes, such as methylation, are one possible mechanism. Epigenetic changes act as intermediaries between the mother’s environment and the child’s DNA, adjusting gene activity without actually altering the genome.
To learn more, the researchers studied a mouse model of maternal allergic asthma developed by Paul Ashwood, professor in the Department of Medical Microbiology and Immunology and senior author on the paper. The model exhibits repetitive and other behaviors similar to ASD.
“You have this maternal allergic asthma event during pregnancy, and then you have these very long-lasting effects on the offspring’s behavior,” said Vogel Ciernia. “We wanted to figure out what some of these long-term effects might be driven by. We looked at immune cells in brain, which we thought might be contributing to these effects.”
The team analyzed methylation and gene expression changes in microglia and found significant variations, affecting immune signaling, inflammation and microglial development. In addition, genes associated with synaptic development also were affected. Variations in these genes are sometimes found in people who develop ASD.
“This is an environmental model, but we’re coming back to the same genes that can be genetically mutated and cause autism in rare cases,” said Janine LaSalle, professor in the Department of Medical Microbiology and Immunology and corresponding author. “That overlap with some of the genes was pretty striking.”
This work showcases the interdisciplinary partnership between the Ashwood and LaSalle labs. Ciernia worked closely with Milo Careaga, an ARTP fellow, Ashwood lab postdoc and second author on the paper.
“They had the immunology expertise and the model, and we had the epigenetics and epigenomics,” said Ciernia.
By exposing the role microglial epigenetics may play in ASD, the paper provides a potential therapeutic strategy. However, the researchers warn that these epigenetic mechanisms must be better understood before pursuing treatments.
“The ultimate goal would be to identify the pathways that are impacted, which could be a therapeutic target to reverse it and potentially improve behaviors,” said Ciernia. “But we need to have a better handle on whether these changes are driving the condition or the result of a compensatory model.”
This work was funded by the NIH (T32MH073124-06, 3R01NS081913-11S1, 829 R21HD086669, R21ES025560, IDDRC U54 HD079125 and 830 5R01NS081913-14), International Rett Syndrome Foundation, Autism Speaks Foundation (7567), NARSAD Foundation, Peter Emch Foundation and the Jane Botsford Johnson Foundation.