It’s all about balance. How a reduction in inhibitory signals in the developing brain could contribute to cognitive deficits in ASD.
or technically,
Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD.
[See Original Abstract on Pubmed]
Authors of the study: Russell G. Port, William Gaetz, Luke Bloy, Dah-Jyuu Wang, Lisa Blaskey, Emily S. Kuschner, Susan E. Levy, Edward S. Brodkin, and Timothy P.L. Roberts
Autism spectrum disorder (ASD) is a developmental disorder characterized by difficulty with social communication and repetitive behaviors.1 ASD persists for one’s entire life, with an estimated 1-2% of children currently diagnosed.1 This is a twenty- to thirty-fold increase from the prevalence recorded in the late 1960s, when ASD was first characterized.1 Experts believe that this sharp increase is mainly due to the fact that doctors and parents are more aware of ASD and what the symptoms look like.2 Despite the fact that people who have ASD are born with the disorder, ASD is hard to diagnose in babies and is often unnoticed until the child begins falling short of social or academic benchmarks.1 The ability to detect autism earlier in young children could make a big difference in how much doctors are able to do to improve the lives of those patients. Russ Port and his graduate advisor Timothy Roberts designed this study to learn more about what makes the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of people with ASD different from those of people who do not have ASD. The results of this study show promise for improving our ability to detect ASD earlier than is currently possible.
Russ knew that researchers in the field believed that ASD may be related to differences in how cells in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. communicate with one another. The brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is made up of specialized cells called neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that can send information to one another via electrical and chemical signals. In order for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to function normally, it must maintain a very careful balance between so-called ‘excitatory’ and ‘inhibitory’ chemical signals. Excitatory signals cause information to move from one neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to the next, while inhibitory signals stop information from moving on to the next neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles (think red/green lights in traffic signals). You need both kinds of signals to make sure that information ends up reaching its proper destination. The most important inhibitory chemical signal is called GABA. Scientists have found that people with ASD have less GABA in their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. than people who do not have ASD. This leads to an imbalance between those excitatory and inhibitory signals in these people.
The electrical signals made by neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles sending information to one another can be measured from the scalp using electroencephalography. When a large group of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles is working together at the same time, they create waves of electrical signals called brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves. One kind of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. wave, gamma-band brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves (Gamma) are relatively fast, compared to the others. To get a better sense of what that means, see figure 1 below. You have the most Gamma in your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. when you are really alert: for example, during learning or sensory input (smell, taste, touch, etc.). The creation of Gamma is dependent upon proper levels of GABA during brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. Since GABA is so important for the creation of Gamma, it may not surprise you to learn that Gamma, like GABA, are also reduced in people with ASD.
Russ knew that researchers in the field believed that ASD may be related to differences in how cells in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. communicate with one another. The brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is made up of specialized cells called neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles that can send information to one another via electrical and chemical signals. In order for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to function normally, it must maintain a very careful balance between so-called ‘excitatory’ and ‘inhibitory’ chemical signals. Excitatory signals cause information to move from one neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles to the next, while inhibitory signals stop information from moving on to the next neuronA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles (think red/green lights in traffic signals). You need both kinds of signals to make sure that information ends up reaching its proper destination. The most important inhibitory chemical signal is called GABA. Scientists have found that people with ASD have less GABA in their brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. than people who do not have ASD. This leads to an imbalance between those excitatory and inhibitory signals in these people.
The electrical signals made by neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles sending information to one another can be measured from the scalp using electroencephalography. When a large group of neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles is working together at the same time, they create waves of electrical signals called brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves. One kind of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. wave, gamma-band brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. waves (Gamma) are relatively fast, compared to the others. To get a better sense of what that means, see figure 1 below. You have the most Gamma in your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. when you are really alert: for example, during learning or sensory input (smell, taste, touch, etc.). The creation of Gamma is dependent upon proper levels of GABA during brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. Since GABA is so important for the creation of Gamma, it may not surprise you to learn that Gamma, like GABA, are also reduced in people with ASD.
Figure 1. Brain waves (waveforms adapted from www.themusiciansbrain.com)
Russ wanted to look at this relationship between GABA and Gamma in his patients with ASD. He confirmed that participants who had ASD had lower levels of both GABA and Gamma than participants who did not have ASD. Interestingly, he also noticed that, in participants without ASD, those with more GABA also had more Gamma, and those with less GABA had less Gamma. In participants with ASD, no such relationship existed.
Excited about this unexpected result, Russ wondered why this relationship between levels of GABA and Gamma was absent in participants with ASD. He thought that it might have something to do with the way the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of people with ASD develop. Therefore, in the next part of the study, he decided to study young people and adults separately. He hypothesized that he would find age-related differences in the relationship between Gamma and GABA that would shed more light on the developmental differences between people with and without ASD. In this part of the study, he found that there was no difference in the levels of Gamma between young people with and without ASD. However, the young people with ASD had lower levels of GABA than those without ASD. We know that GABA is important for the development of Gamma in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of young people. We also know that adults with ASD do have lower levels of Gamma than adults without ASD. The finding that there is a lower level of GABA in young people with ASD but not a lower level of Gamma is an important finding because it suggests that something happens during brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development that causes levels of Gamma in adults with ASD to be lower than what is seen in adults without ASD.
Russ also found that, in young people without ASD, the older a participant was, the more GABA and Gamma they had. This relationship was not present in young people with ASD. In this group, there was no correlation between levels of GABA or Gamma and age. So, in young people with ASD, there isn’t the same increase in both GABA and Gamma as the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. develops that is seen in young people without ASD. Furthermore, Russ found that there was no relationship between levels of GABA and Gamma with age in either adult group. This suggests that once the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is finished developing, the levels of GABA and Gamma stop increasing. With low GABA to begin with, young people with ASD are not able to create enough Gamma to match the levels of people without ASD before the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. stops developing. These lower levels of Gamma become permanent in adulthood.
Broadly speaking, these data are a great case study for the importance of balance between inhibitory and excitatory signals in the developing brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Specifically, Russ’s work highlights the importance of the inhibitory signal GABA during early brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. This work also suggests that monitoring the levels of GABA and Gamma in young children could be used as a possible screening tool to detect ASD earlier. Earlier detection could help doctors develop more effective interventions or strategies for children with ASD and their families.
Excited about this unexpected result, Russ wondered why this relationship between levels of GABA and Gamma was absent in participants with ASD. He thought that it might have something to do with the way the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of people with ASD develop. Therefore, in the next part of the study, he decided to study young people and adults separately. He hypothesized that he would find age-related differences in the relationship between Gamma and GABA that would shed more light on the developmental differences between people with and without ASD. In this part of the study, he found that there was no difference in the levels of Gamma between young people with and without ASD. However, the young people with ASD had lower levels of GABA than those without ASD. We know that GABA is important for the development of Gamma in the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of young people. We also know that adults with ASD do have lower levels of Gamma than adults without ASD. The finding that there is a lower level of GABA in young people with ASD but not a lower level of Gamma is an important finding because it suggests that something happens during brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development that causes levels of Gamma in adults with ASD to be lower than what is seen in adults without ASD.
Russ also found that, in young people without ASD, the older a participant was, the more GABA and Gamma they had. This relationship was not present in young people with ASD. In this group, there was no correlation between levels of GABA or Gamma and age. So, in young people with ASD, there isn’t the same increase in both GABA and Gamma as the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. develops that is seen in young people without ASD. Furthermore, Russ found that there was no relationship between levels of GABA and Gamma with age in either adult group. This suggests that once the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is finished developing, the levels of GABA and Gamma stop increasing. With low GABA to begin with, young people with ASD are not able to create enough Gamma to match the levels of people without ASD before the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. stops developing. These lower levels of Gamma become permanent in adulthood.
Broadly speaking, these data are a great case study for the importance of balance between inhibitory and excitatory signals in the developing brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Specifically, Russ’s work highlights the importance of the inhibitory signal GABA during early brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. This work also suggests that monitoring the levels of GABA and Gamma in young children could be used as a possible screening tool to detect ASD earlier. Earlier detection could help doctors develop more effective interventions or strategies for children with ASD and their families.
About the brief writer: Brenna Shortal
Brenna is a third year student in Alex Proekt’s lab. She is studying the similarities and differences between sleep and anesthesia with the goal of understanding how we wake up.
Citations:
Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators. “Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010.” Morbidity and Mortality Weekly Report: Surveillance Summaries, vol. 63, no. 2, 2014, pp. 1–21.
Stephen J. Blumberg, Matthew D. Bramlett, Michael D. Kogan, Laura A. Schieve, Jessica R. Jones, Michael C. Lu. “Changes in Prevalence of Parent-Reported Autism Spectrum Disorder in School-Aged U.S. Children: 2007 to 2011-2012. National Center for Health Statistics Reports.” National Center for Health Statistics, number 65, 2013.