Yale School of Medicine (YSM) scientists have discovered a molecular difference in the brains of autistic people compared to their neurotypical counterparts.
Autism is a neurodevelopmental condition associated with behavioral differences including difficulties with social interaction, restrictive or intense interests, and repetitive movements or speech. But it’s not clear what makes autistic brains different.
Now, a new study in The American Journal of Psychiatry has found that brains of autistic people have fewer of a specific kind of receptor for glutamate, the most common excitatory neurotransmitter in the brain. The reduced availability of these receptors may be associated with various characteristics linked to autism.
“We have found this really important, never-before-understood difference in autism that is meaningful, has implications for intervention, and can help us understand autism in a more concrete way than we ever have before,” says James McPartland, PhD, Harris Professor of Child Psychiatry and Psychology in the Child Study Center at YSM and the study’s co-principal investigator.
Signaling imbalance in autism
Neurons in the brain communicate with one another using electrical signals and chemical messengers called neurotransmitters. When an electrical current propagates through a neuron, it prompts the release of neurotransmitters that relay a signal to other neurons. This signaling in the brain can be either excitatory or inhibitory. Excitatory signaling primarily triggers the release of the neurotransmitter glutamate, and it acts as a green light telling other neurons to fire. Inhibitory signaling, on the other hand, acts as a brake that suppresses activity.
The brain needs a precise balance of these two types of signaling in order to function properly. One of the leading hypotheses on the underlying causes of autism is an imbalance of excitatory and inhibitory signaling in the brain. Researchers propose the involvement of this central mechanism might explain the wide range of differences observed among autistic individuals.
Based on this hypothesis, the researchers used magnetic resonance imaging (MRI) and positron emission tomography (PET) to look for differences in the brains of 16 autistic adults and 16 people considered neurotypical. MRI scans enabled the researchers to examine the anatomy of each of the participants’ brains, while PET scans revealed how the brains were functioning at the molecular level.
“PET scans can help us pinpoint a molecular map of what’s going on in this glutamate system,” says David Matuskey, MD, associate professor of radiology and biomedical imaging at YSM, and co-principal investigator of the study.
Autistic brains have reduced availability of a crucial receptor
These analyses revealed less brain-wide availability of a specific kind of glutamate receptor, known as metabotropic glutamate receptor 5 (mGlu5) in autistic participants. The findings support the idea that an imbalance of excitatory and inhibitory signals in the brain could be contributing to traits associated with autism, the researchers say.
Fifteen of the autistic participants also underwent an electroencephalogram (EEG), a measure of electrical activity of the brain. Based on the EEG, the researchers identified that these electrical measurements were associated with lower mGlu5 receptors.
This finding could have significant clinical implications, the researchers say. While PET scans are a powerful tool for studying the brain, they are also costly and involve exposure to radiation. EEG could be a cheaper and more accessible way to further investigate excitatory function in the brain.
“EEG isn’t going to completely replace PET scans, but it might help us understand how these glutamate receptors might be contributing to the ongoing brain activity in a person,” says Adam Naples, PhD, assistant professor in the Child Study Center at YSM and the study’s first author.
The study gives the researchers novel mechanistic insight into how the brains of autistic individuals are different from those of neurotypical people. Because the molecular underpinnings of autism are still so poorly understood, clinicians today rely on behavioral observation to diagnose it. Elucidating the “molecular backbone” of autism, researchers say, could potentially lead to better diagnostic tools and ways to support autistic people.
“Today, I go into a room and play with a child to diagnose autism,” says McPartland, “Now, we’ve found something that is meaningful, measurable, and different in the autistic brain.”
There are currently no medications that treat the difficulties experienced by many with autism. The findings could also help researchers come up with therapeutics for autism that target the mGlu5 receptor. While many neurodivergent people aren’t hindered by autism and may not need or want medication, novel treatments could help those on the spectrum that experience symptoms that affect their quality of life.
Future research directions
The current study only included autistic adults. It is still unclear whether the lower receptor availability is a driver of autism or a result of living with it for decades. Previously, research involving PET scans has been limited to adults due to the risks associated with radiation exposure. But Matuskey, co-investigator Richard Carson, PhD, and their colleagues have developed more sophisticated techniques that open a pathway for much lower exposure to radiation.
In future studies, the team plans to conduct research with these new technologies in children and adolescents. “We want to start creating a developmental story and start understanding whether the things that we’re seeing are the root of autism or a neurological consequence of having had autism your whole life,” says McPartland.
All autistic participants in the study had average or above average cognitive abilities. McPartland and collaborators are also working together on developing other approaches to PET scans that will enable them to include individuals with intellectual disabilities in future studies.
