Summary: Autistic adults show reduced availability of a key glutamate receptor, mGlu5, across widespread brain regions. This difference supports the theory that an imbalance between excitatory and inhibitory signaling may contribute to autism-related traits.
EEG data also showed that electrical activity linked to lower receptor availability can be detected noninvasively, suggesting a more accessible way to study excitatory function in autism. These findings offer rare molecular insight into autism and open potential avenues for improved diagnostics and targeted therapeutics.
Key Facts
- Reduced Receptors: Autistic adults showed lower availability of the mGlu5 glutamate receptor across the brain.
- Excitation–Inhibition Link: Findings support the idea that altered excitatory–inhibitory signaling contributes to autistic traits.
- EEG Potential: EEG markers correlated with receptor differences, pointing toward a more accessible diagnostic tool.
Source: Yale
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.
Key Questions Answered:
A: They discovered reduced availability of the mGlu5 glutamate receptor, which plays a central role in excitatory signaling.
A: It supports the long-standing hypothesis that autism involves an imbalance between excitatory and inhibitory brain signaling, which may explain a range of traits.
A: Yes. EEG patterns associated with receptor differences suggest a more accessible diagnostic pathway, and mGlu5-related therapeutics may become future treatment targets.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this autism and neuroscience research news
Author: Isabella Backman
Source: Yale
Contact: Isabella Backman – Yale
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Imaging Metabotropic Glutamate Receptor 5 and Excitatory Neural Activity in Autism” by James McPartland et al. American Journal of Psychiatry
Abstract
Imaging Metabotropic Glutamate Receptor 5 and Excitatory Neural Activity in Autism
Objective:
Autism spectrum disorder is a prevalent and heterogeneous condition with features ranging from social and communication differences to sensory sensitivities. Differences in excitatory neurotransmission have been identified in autism, but the molecular underpinnings are poorly understood.
To investigate the mechanism underlying these observed differences, the authors assessed glutamatergic receptor density in autistic adults using positron emission tomography (PET) and related it to a functional EEG measure of excitatory activity.
Methods:
Metabotropic glutamate receptor 5 (mGlu5) availability was compared in autistic (N=16) and neurotypical (N=16) adults between 18 and 36 years of age, using the PET tracer 3-[18F]fluoro-5-(2-pyridinylethynyl) benzonitrile ([18F]FPEB). The PET outcome measure was volume of distribution (VT) computed with equilibrium analysis using a venous input function and partial volume correction.
Group differences were quantified using mixed-model analyses. Heterogeneity was further parsed within the autistic group by quantifying the relationship between receptor availability and the slope of the EEG power spectrum, an index of excitatory-inhibitory balance. Correlations between EEG and VT were calculated using Spearman’s rho.
Results:
Across all brain regions, mGlu5 availability was significantly lower (by ~15%) in autistic relative to neurotypical control participants. Group differences were generally greatest in the cerebral cortex. Within the autistic group, mGlu5 availability in all regions was significantly correlated with the slope of the EEG (e.g., cerebral cortex, r=0.67), such that shallower slope was associated with lower mGlu5 availability.
Conclusions:
This brain-wide investigation of mGlu5 availability with PET revealed pervasive lower mGlu5 availability across multiple brain areas in autism. Additionally, multimethod analyses revealed associations with a noninvasive electrophysiological index of excitatory neurotransmission.
These results indicate that lower brain-wide mGlu5 availability may represent a molecular mechanism underlying altered excitatory neurotransmission that has the potential to stratify the heterogeneous autism phenotype.
