According to a recent study incorporating human brain tissue and organoids, microglia support the growth and survival of young GABAergic interneurons through the secretion of insulin-like growth factor 1 (IGF-1). These findings suggest a possible origin for the brain signaling imbalances observed in autism and similar conditions.

Prior research has established the involvement of microglia in brain development, though their precise function remained elusive. While some studies indicated that these cells prune neural circuits, subsequent investigations have challenged this theory.

damon Page, principal investigator at Seattle Children’s Research Institute, notes that the new research “identifies microglia as really an important source of IGF, and one that sets the supply of GABAergic interneurons in the developing brain.” Page, who was not involved in the current study, previously led research demonstrating that IGF-1 prevents microcephaly in a mouse model of autism when administered shortly after birth.

he adds that this latest study “extends back that window into the embryonic period,” which has implications for understanding both typical development and conditions such as autism.The findings were published on August 6 in Nature.

The research team employed staining techniques to locate microglia within the medial ganglionic eminence, the site of interneuron formation, in human brain tissue samples across various developmental stages. Early on, microglia were scattered throughout the brain matter. Later, however, these cells clustered around GABAergic neuroblasts, extending their processes into these clusters.The microglia also aligned with radial glia, which are precursors to many types of brain cells.

Based on available data, IGF-1 was identified as the most probable chemical mediator of microglia’s effects on developing cell types. The team also discovered that the cells secreted IGF-1 in organoid models of the developing human brain.

Organoids lacking typical microglia, or containing microglia deficient in IGF-1, exhibited considerably fewer GABAergic interneurons.Typical proliferation was restored when the IGF-1 knockout organoids were treated with IGF.

if there’s ways to keep microglia healthy or rescue them once they have been compromised, I think this would be groundbreaking.

Xianhua Piao, professor of pediatrics at the University of California, San francisco, and a study investigator, stated that the lack of impact on interneuron proliferation when microglial IGF-1 was knocked out in the medial ganglionic eminence of developing mouse embryos was the most unexpected result. She suggests that the microglial IGF-1 mechanism might potentially be specific to humans, given that humans have significantly more interneurons than mice.

Piao, who also works as a neonatologist, notes that severe infection during pregnancy elevates the risk of autism in children, and the study’s results point to a gene-surroundings interaction as a possible mechanism.

She hypothesizes that inflammation,as an environmental factor,could impede how microglia support GABAergic interneuron development,notably in the presence of multiple genetic factors. Her lab intends to introduce inflammation into organoids to observe the response of microglia and IGF-1 pathways.

Marie-Ève Tremblay, professor of neurobiology at the University of Victoria in Canada, who was not involved in the research, suggests that IGF-1 presents a promising treatment avenue, as infections and other forms of inflammation during pregnancy are frequently enough tough to prevent. “If there’s ways to keep microglia healthy or rescue them once they have been compromised, I think this would be groundbreaking.” Trofinetide, a synthetic form of IGF-1, has already been approved by the U.S. Food and Drug Governance for the treatment of rett syndrome.

Tremblay also highlights an important question for future research: whether microglia support GABAergic interneuron development differently in males and females.”Most immune mechanisms differ between sexes,” she says. “If there’s a difference there, it could also help to understand why autism has this sexual dimorphism.”