Contrary to previous research, γ-aminobutyric acid type A (GABAA) receptors are not deficient in the brains of adults with autism spectrum disorder (ASD), although GABA signaling may be functionally impaired, new research suggests.
The idea that a deficiency in GABAA may provide a therapeutic target in ASD is currently under investigation, the researchers note. In two separate imaging studies, they used positron-emission tomography (PET) and two molecular tracers that bind to GABAA receptors to compare their availability in 27 adult nondisabled ASD patients who were not taking medication with 31 control persons.
They found no difference in GABAA receptor availability between the ASD and the control group and no association between receptor availability and performance on several cognitive and social tests.
However, adults with ASD did display altered performance on a GABA-sensitive perceptual task, suggesting that, although GABAA receptor availability may be normal in adults with ASD, GABA signaling may be functionally impaired.
"We found no difference in overall GABAA receptor binding or the α1 or α5 subunits in humans or in three rodent models of idiopathic autism," study coauthor Declan Murphy, MD, professor of psychiatry and brain maturation and director of the Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, King's College London, United Kingdom, told Medscape Medical News.
"GABAA receptor binding in adults with ASD who do not have ID [intellectual disability] or epilepsy is normal, so efforts to pursue this as a drug target need to be reassessed," he said.
The study was published online October 3 in Science Translational Medicine.
There is increasing evidence of a deficit in inhibitory GABA in patients with ASD. The evidence comes from in vivo and imaging studies of ASD using [1H] proton magnetic resonance spectroscopy, the authors write.
Alterations in the expression of GABA receptors, of which GABAA is the most prevalent type in the brain, may be a key contributor to the excitatory/inhibitory imbalance in ASD, they suggest.
Moreover, previous research found reductions in the density of GABAA receptors in several brain regions post mortem, but sample sizes were small and included individuals taking medications (eg, anticonvulsants) that might have altered GABAA expression.
"What motivated our study was the idea that GABAA may provide a therapeutic target [in ASD], an idea that is being pursued by many laboratories and some pharma companies," Murphy reported.
"As part of that, it needed to be determined if GABAA receptor binding is or is not abnormal," he said.
To facilitate that process, it is "crucial for laboratories to work together to attack the same/related questions — but from different angles — in order to make more rapid progress by running these studies at the same time, so we worked together with the Karolinska Institutet to do this," he said
"Typically, in the past, one laboratory would carry out a study, such as looking at GABAA in rodents, and another would attack a similar question in humans, and another would look at GABAA 1,5 in rodents, and yet another in humans, but this process takes many years," he noted.
"We speeded up that process by coordinating our efforts as part of the EU-AIMS [European Autism Interventions Multicenter Study] study," he said.
To investigate the GABAA receptors in human beings, the researchers conducted two PET imaging studies in two independent clinical centers in Stockholm, Sweden, and London, using a different tracer in each center ([11C]flumazenil and [11C]Ro15-4513, respectively).
They selected three rodent models of ASD that represented a range of genetic risk factors for ASD in humans: mice lacking Cntnap2, mice lacking Shank3, and mice carrying a genetic deletion equivalent to deletion of human chromosome 16p11.2.
The same radiotracers that were used in the human PET studies were used in the mice, and autoradiography was performed to quantify GABAA receptors in the mouse brain.
No Receptor Binding Differences in ASD
No difference between adults with and those without ASD was found in GABAA receptor availability using PET imaging with the [11C]flumazenil tracer. There were no differences in the binding potential of [11C]flumazenil in the whole brain (P = .203), brain tissue gray matter (P = .210), or in 13 specific brain regions (all P > .16) between the two groups.
The findings remained, even after sensitivity analyses that corrected for partial volume effects, inclusion of male participants only, and exploratory voxel-wise analysis.
Moreover, there were no differences between the London and Stockholm cohorts in terms of age or intelligence quotient (IQ).
Participants in the [11C]flumazenil Stockholm cohort completed a battery of tests designed to explore executive function, central coherence, and social cognition.
No correlation was found between GABAA receptor availability in the gray matter of either the ASD or the control group in cognitive, social, and central coherence tasks.
However, the performance of the ASD group was significantly lower than the control group on letter fluency (P = .006), alterations between categories (P = .001), and all social cognitive tasks.
When the researchers used the [11C]Ro15-4513 tracer for PET imaging and the two-tissue compartment model, they found no group differences between adults with and those without ASD in total [11C]Ro15-4513 binding in the whole brain (P = .176), gray matter (P = .614) or in 11 of the 13 specific brain regions (all P > .1) they examined.
In a secondary analysis of the [11C]Ro15-4513 binding data, nonlinear spectral analysis was used to distinguish between GABAA receptor -α5 non-α5 subunit availability.
No differences were found in the total brain or regional availability of either subunit in adults with ASD vs control persons.
Of note, no differences in α5 subunit availability were observed in the hippocampus or amygdala (P > .3) — areas in which significant differences had been detected in a previous pilot study.
Additionally, there was no difference in age or IQ between adults with ASD and the control individuals.
"We did not find any detectable differences in GABAA receptor availably using the tracers [11C]flumazenil and [11C]Ro15-4513 and PET imaging in adults with and without ASD," the authors summarize
Availability vs Binding
In vitro autoradiography was used to detect GABAA receptor availably in brain tissue from the three mouse models of ASD: mice lacking Cntnap2, mice lacking Shank3, and mice with a 16p11.2 deletion.
Bilateral examination of brain tissue from six brain regions — the frontal cortex, the cingulate cortex, the caudate/putamen, the dorsal hippocampus, the cerebellum, and the amygdala — revealed no significant differences in the specific binding of either the [3H]flumazenil tracer or the [3H]Ro15-4513 tracer in brain tissue from any of the three mouse models compared to wild-type animals (all P > .05)
Examination of the left and right amygdala separately yielded no significant differences in binding with either tracer in any of the three ASD mouse models.
There were no significant differences or trends found in the 16p11.2 deletion mouse model.
To complement the PET imaging measures of GABAA receptor availably and rodent findings, the researchers used the paradoxical motion perception (PMP) task, an established proxy measure of GABA signaling in the visual cortex, to compare GABA signaling in adults with and those without ASD.
The PMP effect was found to be present in adults with and those without ASD; however, the magnitude of the contrast-induced motion perceptual impairment ratio was reduced in the ASD group compared to the control group.
The ASD patients "showed a selective enhancement in motion perception under conditions of high contrast, results considered consistent with a defect in GABA signalling," the authors summarize.
Murphy noted that the study focused only on a specific subgroup of people with ASD, and it is "possible that others — for example, with ID or epilepsy —do have differences in GABAA receptor binding."
The GABA Story Needs to Be Amended
Commenting on the study for Medscape Medical News, Gene Blatt, PhD, director of neuroscience, Hussman Institute for Autism, Baltimore, Maryland, who was not involved with the study, called it "important" because it "comes from two different cohorts of subjects — one from London and one from Stockholm — with similar results."
The results might help to explain "why GABAA-based drugs are effective in some individuals and not in others," he continued.
"By eliminating those with a history of seizures and those taking medications for seizures, these confounding variables have been eliminated, yielding more accurate results," he suggested.
"Previous postmortem studies by the Blatt lab demonstrated decreases in GABAA receptor densities in specific layers of key cerebral cortical areas in autism cases compared to controls. Thus, a deeper analysis of autism sections is necessary to better discern how local connectivity is affected in the autism brain disturbing excitatory/inhibitory imbalance," Blatt said.
Also commenting on the study for Medscape Medical News, Frank Kooy, PhD, professor of cognitive genetics, Department of Medical Genetics, University of Antwerp, Belgium, who was not involved with the study, called it "technically sound work" with "methodology that adds knowledge to previous studies."
The finding of abnormalities in GABAergic functioning in autistic patients was "very intriguing.... The key next question is what causes these abnormalities," he said.
Murphy agreed. "In the context of normal receptor binding, autistic individuals still have abnormalities in GABA-ergic function, so what we need to do now is to find out what is driving those differences,"
"The GABA story' is not 'dead,' but it needs to be amended," Murphy added.
The study was funded by EU AIMS and AIMS-2-TRIALS. EU-AIMS receives support from the IMI Joint Undertaking (JU), resources of which are composed of financial contribution from the European Union ' s Seventh Framework Programme, from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies ' in kind contribution, and from Autism Speaks. Additional information about funding can be found in the original article. Dr Murphy, Dr Blatt, and Dr Kooy have disclosed no relevant financial relationships. Disclosures of financial relationships from the other study authors can be found on the original article.
Sci Transl Med. Published online October 3, 2018. Abstract
Medscape Medical News © 2018
Cite this: PET Scans Show No Brain GABA Receptor Deficiency in Autism - Medscape - Oct 19, 2018.