Abnormalities in a type of brain cell called astrocytes may play a central role in causing certain behavioral symptoms of autism spectrum disorders, according to a preclinical study by researchers at Weill Cornell Medicine.
For the study, published April 1 in Molecular Psychiatry, Lead author Dr. Dilek Colak, assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, and colleagues grew astrocytes from stem cells derived from autism patients and transplanted them into mice. healthy newborns. They found that after the transplant, the mice developed repetitive behaviors, a hallmark symptom of autism spectrum disorder (ASD), but did not develop the social deficits associated with the disease. The mice also developed memory deficits, which are commonly seen in ASD but are not a core feature of the disease.
“Our study suggests that astrocyte abnormalities may contribute to the onset and progression of autism spectrum disorders,” said Dr. Colak, who is also an assistant professor of pediatric neuroscience and a fellow at the Drukier Institute for Children’s Health. “Abnormalities of astrocytes may be responsible for repetitive behaviors or memory deficits, but not other symptoms such as difficulties in social interactions. »
Most studies of autism spectrum disorders have focused on the role of neurons, a type of brain cell that relays information in the brain. But other brain cells, called astrocytes, help regulate the behavior of neurons and the connections between them. Gene mutations linked to autism spectrum disorders are likely to affect different brain cell types differently, Dr. Colak said. Post-mortem studies had previously revealed astrocyte abnormalities in the brains of patients with autism spectrum disorders.
“We didn’t know if these astrocyte abnormalities contributed to disease development or if the abnormalities were a result of the disease,” Dr. Colak said.
To determine if astrocytes might be involved early in the disease, the team obtained stem cells derived from patients with autism spectrum disorders, persuaded them to develop into astrocytes in the lab, and transplanted them into the brain of otherwise healthy newborn mice, creating a human-chimera mouse.
Using a microscopic technique called two-photon imaging, they observed excessive calcium signaling in human astrocytes transplanted into mouse brains, explained co-lead author Dr. Ben Huang, a neuroscience instructor in psychiatry at Weill Cornell. Medical.
“It was amazing to see these human astrocytes respond to behavioral changes in active mice,” Dr. Huang said. “We believe that we are the first to record the activity of human astrocytes transplanted in this way. »
To determine whether increased calcium signaling caused the behavioral symptoms in the mice, the team infected astrocytes cultured from stem cells of ASD patients in the lab with a virus carrying an RNA fragment designed to reduce calcium signaling to normal levels. When they transplanted these astrocytes into mice, the animals did not develop memory problems.
“Future therapies for autism could exploit this finding by using genetic tools to limit extreme calcium fluctuations inside astrocytes,” said co-lead author Megan Allen, postdoctoral neuroscience associate at Feil Family Brain. and Mind Research Institute of Weill Cornell Medicine.
The findings may also have important implications for understanding and treating other neuropsychiatric illnesses like schizophrenia that also involve memory deficits, Dr. Colak said.
“It is important to determine the roles of specific types of brain cells, including astrocytes, in neurodevelopmental and neuropsychiatric diseases,” she said.
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