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An Investigation of the Role of the Brain GABA-Benzodiazepine Receptor Alpha-5 Subtype in Autism Spectrum Disorder Using the Benzodiazepine Inverse Agonist PET Ligand [11C]Ro15-4513

Thursday, 2 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
M. A. Mendez1,2, J. Horder1, J. F. Myers3, S. Coghlan1, P. R. Stokes2, D. Erritzoe2, O. Howes4, A. Lingford-Hughes2, D. J. Nutt2 and D. G. Murphy1, (1)Forensic and Neurodevelopmental Sciences Department, Institute of Psychiatry. King's College London, London, United Kingdom, (2)Centre for Neuropsychopharmacology, Division of Brain Sciences, Dept of Medicine, Imperial College London, London, United Kingdom, (3)Psychopharmacology Unit, Bristol University, Bristol, United Kingdom, (4)Psychiatric Imaging Group, MRC Clinical Sciences Centre, London, United Kingdom

The biological associates of clinical symptoms in Autism Spectrum Disorders (ASD) are poorly understood. An imbalance between gamma-aminobutyric acid (GABA) and glutamate neurotransmission has been suggested to be responsible for the impaired information processing and social behavior described in autism. However, relatively few studies have directly examined brain GABA or glutamate in people with ASD. Recent neurochemical research has focused on the GABA system in a number of limbic regions and its possible causal relationship with symptoms in people with ASD. Nobody has yet directly examined the in vivo availability of brain GABA A receptors in adults with ASD, or related variation in GABA A receptors to symptoms.


To measure α1 and α5 GABA-A subtype receptor levels in limbic regions frequently implicated in ASD: the amygdala-hippocampal complex, basal ganglia and anterior cingulate cortex, using Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [11C]Ro-15-4513.


Three volunteers diagnosed with Asperger’s Syndrome matching the ICD-10 criteria who scored above threshold for ASD in the Autism Diagnostic Observation Schedule (ADOS) and three age-sex matched controls underwent 90 minute, fully quantified [11C]Ro15-4513 PET scans. Structural MRIs were used to localize radioligand binding to specific brain regions. Spectral analysis was used to quantify volume of distribution (VT) in individual regions of interest, and the contribution of ligand binding at the α1- and α5- containing GABA-A receptor subtypes.


A two-way ANOVA showed significantly lower VT across all regions in the brains of participants with ASD comparing to controls (F=140.7, p<0.0001). This effect was largely related to the α5-containing subtype (F=32.27, p<0.0001). Further Student t-tests showed significant lower binding in nucleus accumbens (t=3.360, p<0.05) and amygdala (t=3.684, p<0.05), and a similar trend in hippocampus and the anterior cingulate gyrus.


The abnormalities within the limbic system found in this study may explain some of the social and emotional difficulties observed in people with ASD, specifically Asperger’s Syndrome, as GABAergic neurons are fundamental for the processing of information in most brain regions.

Though lower levels of α5 appear predominantly responsible for the lower VT, the low signal:noise ratio of these methods of estimating VT at the lower affinity α1-containing subtype, with low subject numbers, limits the certainty of this interpretation. However, the lack of changes in receptor kinetics at either subtype suggests the differences in binding are probably due to down-regulation of receptor expression, supporting previous findings in gene assays.

The understanding of the GABAergic system in more detail through the characterisation of the α5-containing subtype will allow in vivo assessment of the imbalance between the GABA/glutamatergic system that has been postulated in autism and may give us some future guidance in the pharmacological management of ASD.

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