Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder

Abstract

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABA A receptor densities can identify objective molecular markers in ASD. We measured both total GABA A receptor densities by using [ 18 F]flumazenil positron emission tomography ([ 18 F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy ( 1 H-MRS) in 28 adults with ASD and in 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABA A receptor densities between ASD and TD groups. However, 1 H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale – Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Thalamocortical connectivity is associated with autism symptoms in high-functioning adults with autism and typically developing adults

“…Participants were of the same cohort that had been studied in a previous investigation by our lab 24 . We will refer to this cohort as the HFASD cohort.…”

“…Sensorimotor processing may be related to aberrant inhibitory neurotransmission in ASD. Altered cortical inhibition is a widely supported theory in ASD, as evidenced by altered levels of glutamate 22 and GABA 23,24 , and sensory hyper-and hyposensitivity 1 . Neurodevelopmental disorders associated with ASD, such as fragile X Syndrome and Tourette syndrome, also exhibit alterations of cortical inhibition and suggest an involvement of sensorimotor deficits 25,26 .…”

GABA Measurement in a Neonatal Fragile X Syndrome Mouse Model Using 1H-Magnetic Resonance Spectroscopy and Mass Spectrometry

“…1 H-magnetic resonance spectroscopy ( 1 H-MRS) is an MRI technique clinically used to study brain disease (Öz et al, 2014;Wilson et al, 2019), including the measurement of GABA in respect to autism spectrum disorder (Harada et al, 2011;Horder et al, 2018;Fung et al, 2020). 1 H-MRS is capable of non-invasively measuring neurotransmitters and metabolites, in vivo and is typically utilized in conjunction with structural MRI (sMRI) to assess neurochemical composition within brain anatomical regions (Faghihi et al, 2017).…”

“…To date, clinical studies using 1 H-MRS to study GABA in ASD have found a decrease in GABA concentration in the frontal lobe of children with ASD (Harada et al, 2011) while, alternatively found an increase in the dorsal lateral prefrontal cortex in adults with ASD (Fung et al, 2020). PET imaging studies in participants with FXS have found a structurally-dependent decrease in GABA A receptor binding potential primarily for the thalamus (D'Hulst et al, 2015) using 11 C-Flumazenil (FMZ), a GABA A antagonist that binds to the post-synaptic benzodiazepine site of the GABA A receptor, between the α and γ subunits.…”

Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor

“…A collapse of GABAergic transmission leads to neuronal hyperexcitability and the subsequent development of epileptic seizures [ 3 , 4 ]. An aberrant GABAergic system is also associated with neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and autism spectrum disorders (ASD) [ 5 , 6 , 7 ], often co-occurring with epileptic seizures [ 8 , 9 ]. Many anticonvulsants promote GABAergic neuronal transmission by enhancing the activity of the GABA type-A (GABA A ) receptor and increasing GABA content in the synaptic cleft [ 4 , 10 ].…”