Using PET imaging and EEG brain recordings, investigators say they have found a potential mechanism underlying altered excitatory neurotransmission in people with autism.

Such mechanisms are still poorly understood, in part because of the wide range of behavioral and cognitive symptoms experienced by those who are diagnosed. This heterogeneity has made it hard to prove whether there are core mechanisms shared by all patients, or various combinations of mechanisms that manifest in subgroups. Across the wide spectrum of patients, differences are seen in such key areas as sensory experience, sleep patterns, language use, cognition, attention, and motor function. Each of these has a complex mechanistic relationship with different brain regions.

Still, as noted by the researchers, who have reported the new findings in the American Journal of Psychiatry, a leading hypothesis explaining at least some of the diversity of clinical and neuroscientific observations “is that there is a global imbalance of excitatory and inhibitory neurotransmission in the brain that affects neural function in pervasive ways.”

The team, with five members who have received BBRF grants, was co-led by David Matuskey, M.D., a 2009 and 2018 BBRF Young Investigator; and James C. McPartland, Ph.D., a 2009 BBRF Young Investigator. The new paper’s co-first authors are Adam J. Naples, Ph.D., and Yanghong Yang, M.D. All are at Yale University.

Converging evidence from different sources has implicated altered excitatory neurotransmission in autism, the team notes. Seizures, caused by an excess of excitation, are significantly more common in those with autism spectrum disorders (ASDs). Animal models of various syndromes regarded as part of the autism spectrum, such as fragile X syndrome and Rett syndrome, have revealed increased high-frequency oscillatory neural activity (above 30 Hz) in the brain, as measured by EEG. Additionally, PET imaging, which can measure quantities of different neurotransmitters in the brain, has shown regional alterations in glutamate, the most prevalent excitatory neurotransmitter, in autism patients compared with neurotypical individuals. Finally, EEG measures that serve as an index of the balance between excitatory vs. inhibitory neural activity in the brain (often referred to as the E:I balance) has shown both decreased and increased excitatory neural activity in autism patients, a measure that has varied with different study cohorts.

This inconsistency, which has perplexed researchers—especially those who hypothesize that evidence of increased excitation in autism constitutes an important biological correlate—led the team to conduct the study just reported, in which they probed a possible relationship between the function of a key excitatory glutamate receptor called metabotropic glutamate receptor subtype 5 (mGlu5) with EEG brain wave patterns observed in adults with autism.

mGlu5 is a key constituent of the glutamate system. The receptor is located throughout the brain in neurons and helper cells called glia, and plays a central role in modulating communication between these two key cell types as well as processes that regulate neuronal excitability and synaptic plasticity (the strength of connections between neurons).

As noted by the team, mGlu5 has been implicated in the causation of autism. Rare human DNA variants seen in ASD patients have been identified in genes encoding proteins that interact with mGlu5 signaling pathways. Postmortem studies have revealed higher levels of mGlu5 in regions associated with important autism features, including parts of the cerebral cortex. Experiments have been conducted in mice modeling fragile X syndrome in which pharmaceutical inhibition of mGlu5 reverses autism-like behaviors—an effect that has not been replicated, however, in human trials.

To gain more insight into mGlu5’s possible role in autism, the team recruited 16 adults with autism, average age in the mid-20s (11 male), and an equal number of demographically matched neurotypical individuals. Each received a PET scan, which uses a radioactive tracer to determine the presence, in this case, of mGlu5 receptors across the brain. How many such receptors were available for activation in regions thought to be important in autism?

Among the study participants with autism, mGlu5 “availability” across the brain was “significantly lower”—by about 15%, with the greatest differences between groups found in the cortex—compared with neurotypical participants. To explore the possible significance, the researchers quantified the relationship between the number of available mGlu5 receptors and an index of E:I balance in study participants with autism.

This enabled them to discover that pervasive, lower mGlu5 receptor availability in all brain regions in autism patients correlated, generally, with a common EEG index of E:I balance. On this basis, the team said that individual differences in mGlu5 may be a way of stratifying the highly diverse population of people with an ASD—one way of usefully distinguishing subgroups which might, in theory, be responsive to different treatment approaches.

The fact that this study showed mGlu5 differences across the brain, not just in certain regions, in the team’s view “suggests that underlying autism differences are domain-general rather than limited to a particular type of information processing (e.g., sensory or social), or to the mode of sensory information (e.g., vision or hearing).”

Both the mGlu5 receptor and EEG patterns can provide information about the function of multiple brain areas that impact diverse functions, including sensory processing, social interaction, learning, and memory, the team said. Thus, they continued, “our results suggest a mechanism through which differences in [mGlu5] receptor availability may impact cognition and contribute to the multifaceted traits observed in autism.”

If these results can be validated, it may be possible, they said, to use EEG data pertaining to the E:I balance as an inexpensive and easy-to-acquire way of assessing glutamate function and neural excitability in autism patients to complement PET research, which can be costly and involves the use of radioactive tracers.

This may be relevant in stratifying participants for potential clinical trials testing medications targeting mGlu5. At the same time, it will be important, said the researchers, to better identify relationships between mGlu5 receptor availability and the range of characteristics affected by autism. For now, the main insight afforded by their study, they wrote, is providing “strong evidence for the role of glutamate system differences in understanding the biology of autism.”

The team also included: Yiyun Huang, M.D., 1999 BRF Young Investigator; Ansel T. Hillmer, Ph.D., 2020 BBRF Young Investigator; and Irina Esterlis, Ph.D., 2012 and 2007 BBRF Young Investigator.