Inside The Autistic Brain: How Chemical Changes Affect Neural Activity

This study showed that autistic adults exhibit a generalized reduction in mGlu5 receptors, which are fundamental for excitatory communication between neurons. This decrease is directly associated with alterations in brain electrical activity, indicating a possible molecular mechanism behind the differences in brain function in autism. The findings help explain the biological basis of ASD and may contribute to a better characterization of its different profiles.

Autism spectrum disorder, known as ASD, is a very common and highly diverse neurodevelopmental condition. This means that there is no single way to "be autistic": some people have greater difficulties with social interaction and communication, while others have increased sensitivity to sounds, lights, smells, or tactile stimuli. There are also important differences in how the brain processes information.

Although many studies have already shown that the functioning of neurotransmitters, chemical substances that allow communication between neurons, is different in autism, little is still known about the specific molecular mechanisms that explain these differences.

Among the most important neurotransmitters in the brain is glutamate, which is primarily responsible for excitatory communication, that is, the communication that "activates" neurons and allows signals to be transmitted from one cell to another. Previous research had already suggested that excitatory neurotransmission might be altered in autistic individuals, but it was unclear exactly how this occurred in the living human brain.

To investigate this question more directly, the researchers in this study decided to observe a specific type of glutamate receptor in the brain, called the metabotropic glutamate receptor type 5, or mGlu5.

mGlu5 receptors function as "gates" in nerve cells that allow glutamate to exert its effects. The number of these receptors available in the brain can directly influence the level of excitatory neural activity. To measure this, the researchers used an advanced brain imaging technique called positron emission tomography, or PET.

This examination allows visualization and quantification of specific molecules in the living brain. The study included 32 adults between 18 and 36 years old: 16 with a diagnosis of autism and 16 neurotypical, that is, without a diagnosis of ASD.

During the PET scan, a specific radioactive tracer was used, which binds to mGlu5 receptors, making it possible to measure their availability in different regions of the brain. The main measure analyzed was the so-called volume of distribution, which reflects how much of this receptor is available to act. To ensure accuracy, the data were corrected for individual anatomical differences and analyzed using statistical methods that allow for robust comparison between the groups.

In addition to PET scans, the researchers also used electroencephalography, or EEG, which records the brain's electrical activity non-invasively. EEG was used to measure a functional index related to the balance between neural excitation and inhibition, known as the slope of the power spectrum.

In simple terms, this measurement helps to understand whether the brain is functioning in a more excited or more inhibited way. This step was fundamental to connecting the number of receptors observed in the PET scan with the actual functioning of brain activity.

The results showed that, in virtually all brain regions analyzed, autistic individuals had a significantly lower availability of mGlu5 receptors compared to the neurotypical group. This reduction was about 15% on average and was especially evident in the cerebral cortex, a region involved in functions such as thought, perception, language, and social interaction.

In other words, the brains of autistic adults had fewer "gates" available for glutamate action in areas fundamental to behavior and cognition.

When researchers analyzed only the autistic group, they observed something even more interesting. The number of mGlu5 receptors in different brain regions was strongly related to the measurement obtained in the EEG.

In particular, individuals with lower mGlu5 availability showed a less pronounced slope in the power spectrum, indicating a greater imbalance between neural excitation and inhibition. In simple terms, the fewer mGlu5 receptors available, the more altered the excitatory functioning of the brain appeared to be.

These findings are important because they clearly connect, for the first time, a specific molecular alteration, the reduction of mGlu5 receptors, with a functional measure of brain activity in autism. This suggests that the decrease in these receptors may be one of the central biological mechanisms behind the differences in excitatory neurotransmission observed in autistic individuals.

Furthermore, since autism is a very heterogeneous spectrum, this measure can help differentiate subgroups within ASD, contributing to a more personalized understanding of the condition.

Taken together, the study indicates that the lower availability of mGlu5 receptors throughout the brain is not an isolated finding, but a broad and consistent phenomenon in adult autism. These results pave the way for future research exploring mGlu5 as a possible biological marker of autism and, potentially, as a target for therapeutic strategies that seek to modulate excitatory brain activity more precisely.

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Imaging Metabotropic Glutamate Receptor 5 and Excitatory Neural Activity in Autism

Adam J. Naples, Yanghong Yang, Paul Gravel, Takuya Toyonaga, Faranak Ebrahimian Sadabad, Sheida Koohsari, Brian Pittman, Jean-Dominique Gallezot, Lauren Pisani, Caroline Finn, Sophie Cramer-Benjamin, Nicole Herman, Lindsey H. Rosenthal, Cassandra J. Franke, Bridget M. Walicki, M.Eng., Isabel G. Rodden, Ansel T. Hillmer, Irina Esterlis, 

Jim Ropchan, Nabeel Nabulsi, Yiyun Huang,  Julie M. Wolf, Richard E. Carson, James C. McPartland, and David Matuskey

American Journal of Psychiatry, Volume 183, Number 1

https://doi.org/10.1176/appi.ajp.20241084

Abstract:

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. 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. 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. 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.