What genes and brain chemicals teach us about autism

Autism is a topic that concerns many people. Parents, caregivers, professionals, and people with autism themselves often search for answers: where does autism come from? And what happens in the brain?

A new study from Portugal and England provides a piece of the puzzle. The researchers examined genes related to communication between brain cells and substances in the brain important for energy and information transfer.

Their conclusion is that in some people with autism, gene changes affect the balance between glutamate (an excitatory substance) and GABA (an inhibitory substance). These changes are associated with measurable differences in brain metabolism.

In this blog we explain step by step what this means, why it is important and how it fits into broader theories about autism.

What are glutamate and GABA?

To understand what this research is about, we first need to understand two key players. Glutamate is the brain's primary excitatory messenger. It activates brain cells and transmits signals. GABA, on the other hand, is the brain's primary inhibitory messenger. It helps brain cells calm down. You can think of glutamate and GABA as the brain's accelerator and brake. Proper functioning requires a balance between the two. Too much acceleration or too little braking can lead to overstimulation. Too much braking, on the other hand, prevents information from flowing properly. Many researchers believe that a disruption in this balance plays a role in autism.

What did the researchers do?

The researchers combined two types of data. They examined the DNA of children and adolescents with autism and searched for variants in genes important for communication between brain cells (synapses). Some variants were "predicted damaging variants" (PDVs): changes that likely disrupt the function of a gene or protein. They also measured brain chemicals using a special MRI technique called proton magnetic resonance spectroscopy (¹H-MRS).

This allowed them to look inside the brain without surgery or injection. They measured the levels of certain substances, such as tNAA (N-acetylaspartate), a substance that indicates the health and energy of nerve cells; tCr (creatine), a substance related to energy management in the brain; and GLX (glutamate + glutamine) and GABA+, substances directly related to excitatory and inhibitory signals.

Who participated?

Sixteen young people with autism, without intellectual disabilities, participated, as their IQ had to be above 70. There was also a control group of 14 young people without autism. Within the group with autism, a distinction was made between 10 young people with a genetic variant in the genes being studied and 6 young people without such a variant.

What did they find?

The main results were that young people with autism who had a genetic variant in the genes studied had lower levels of tNAA and tCr. These substances are linked to the energy and health of brain cells. There was a clear trend: young people without autism had the highest levels, young people with autism without a genetic variant were in between, and young people with autism and a genetic variant had the lowest levels.

Surprisingly, the researchers found no clear differences in the direct measurements of glutamate and GABA. However, because tNAA and tCr are closely linked to these systems, the results nevertheless point to a disruption in the balance between excitatory and inhibitory signals.

What does this mean?

This research shows that genetic changes in certain brain genes are linked to measurable differences in brain metabolism. This is important because it helps us better understand the biological basis of autism. It confirms that autism is not caused by a single gene or a single cause, but rather by many different pathways that can all contribute.

It supports the theory that a disruption in the balance between glutamate and GABA plays a role. It also opens the door to biomarkers, measurable signals in the brain that can help distinguish subgroups within autism.

Why is this important for practice?

For parents, caregivers, and individuals with autism, this may still be somewhat abstract. Yet, this type of research could have practical implications in the future. It can lead to better diagnoses and subtyping, with brain scans and genetic tests helping to better understand which biological processes are at play in an individual. More targeted treatments could also become possible, for example, if it is known that someone's GABA function is primarily disrupted, which could guide medication or nutritional supplements that may affect this. Moreover, it can create greater understanding, because the idea that autism is linked to measurable biological processes contributes to the recognition that autism is not a parenting error or personality trait, but a neurobiological variation.

Limits of the research

It's also important to note the limitations. The study involved a small group of 16 young people with autism, and the results still need to be confirmed in larger, international studies. Not all genetic variants are equally well understood; some are variants of unknown significance. Furthermore, brain scans measure averages within a brain region, but they don't reveal everything about how brain cells work.

A bridge to the living world

So what can we do with this in everyday life? The research emphasizes that autism is very diverse. One person may primarily experience overstimulation, while another may experience slow information processing. The concept of a balance between accelerating and braking can help better explain autism to children, parents, and teachers. It also demonstrates the need for personalized care, because what works for one person doesn't necessarily work for another.

Imagine the brain as a smart home with a thermostat that constantly regulates the temperature. Glutamate is like a heater: it activates, stimulates, and gets the system moving. GABA is like an air conditioner: it cools, slows, and creates a calming effect. In a well-tuned system, these two work in harmony. The thermostat constantly monitors the environment and adjusts the temperature to maintain a comfortable temperature, regardless of whether it's hot or cold outside.

In some people with autism, this thermostat doesn't function optimally. Genetic changes can cause the heating to come on too often or the air conditioning to react too slowly. The result is an imbalance in the brain's internal climate: too much stimulation, too little rest, or a delayed response to change. This creates an environment in which it's difficult to adapt to new situations, external stimuli, or social cues. Brain metabolism actually reflects these disruptions, as if the thermostat is transmitting readings that don't match actual needs.

This metaphor illustrates that the brain isn't simply "oversensitive," but that its internal regulation of stimuli and calm is disrupted. It's not the outside world that's too loud, but the regulatory system struggling to find the right balance. As a result, everyday situations can feel overwhelming, while the brain is actually trying to maintain a comfortable temperature in a house where the thermostat isn't functioning properly.

Theoretical framework

To place this research in a broader perspective, it's helpful to identify some theoretical frameworks frequently used in autism science. The excitation-inhibition (E/I) balance model posits that autism arises from a disruption in the balance between excitatory (glutamate) and inhibitory (GABA) signals in the brain. The current study supports this model, as genetic variants in these systems are associated with lower levels of tNAA and tCr.

From a neurodiversity perspective, autism is seen as a natural variation in the human brain, not a disorder that needs to be fixed. Research can contribute to this by demonstrating that biological differences explain this diversity, without this necessarily being negative.

The biopsychosocial model emphasizes that biological factors, such as genes and brain chemicals, psychological factors, such as coping and motivation, and social factors, such as support and environment, together determine how someone functions. Research primarily addresses the biological component, but must always be connected to the other layers. Personality and developmental models also play a role, as autism develops in interaction with the environment. Genetic vulnerability can lead to certain brain differences, but how this plays out depends on upbringing, education, and social context.

Conclusion

This study shows that in some young people with autism, genetic variants exist that influence the balance between glutamate and GABA in the brain. These variants are associated with measurable differences in brain chemicals that indicate energy and the health of nerve cells.

In practice, this means we're increasingly understanding that autism doesn't have a single cause, but rather an interplay of genes, brain processes, and environment. The research supports the idea that autism is related to a disruption in the balance between excitatory and inhibitory signals in the brain. This disruption is influenced by genetic variants that affect the energy and health of nerve cells.