Αlpha 5 subunit-containing GABAA receptors in temporal lobe epilepsy with normal MRI

Author:

McGinnity Colm J123ORCID,Riaño Barros Daniela A12,Hinz Rainer4ORCID,Myers James F1,Yaakub Siti N3,Thyssen Charlotte5,Heckemann Rolf A6,de Tisi Jane7,Duncan John S7,Sander Josemir W78,Lingford-Hughes Anne9,Koepp Matthias J7,Hammers Alexander12310

Affiliation:

1. Centre for Neuroscience, Department of Medicine, Imperial College London, London W12 0NN, UK

2. MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK

3. King's College London & Guy's and St Thomas' PET Centre, School of Biomedical Engineering & Imaging Sciences, King’s College London, London SE1 7EH, UK

4. Wolfson Molecular Imaging Centre, University of Manchester, Manchester M20 3LJ, UK

5. Medical Image and Signal Processing (MEDISIP), Department of Electronics and Information Systems, Faculty of Engineering and Architecture, Ghent University, 9000 Ghent, Belgium

6. Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden

7. NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK, and Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0RJ, UK

8. Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede 2103SW, The Netherlands

9. Neuropsychopharmacology Unit, Centre for Psychiatry, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK

10. Neurodis Foundation, CERMEP, Imagerie du Vivant, 69003 Lyon, France

Abstract

Abstract GABAA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [11C]flumazenil has revealed reductions in GABAA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI (‘MRI-negative’) and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [11C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. ‘Bandpass’ exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [VF; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (VS; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of VF and VS measures from a single bolus injection of [11C]Ro15-4513. The epilepsy group had higher VS in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas (P < 0.004). This was associated with reduced VF:VS ratios within the same areas (P < 0.009). Comparisons of VS for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean ± standard deviation −0.4 ± 1.0 versus 0.7 ± 0.3; P = 0.02). In individuals with epilepsy, hippocampal VS did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced VF in the hippocampal area, which was significant ipsilaterally (P = 0.03), as expected from [11C]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from α1/2/3 to α5 in MRI-negative temporal lobe epilepsy.

Funder

Medical Research Council

Clinical Sciences Centre

Department of Health National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme

Medical Research Council Doctoral Training Account

Imperial College London, and subsequently by the Medical Research Council

Wellcome Trust/Engineering and Physical Sciences Research Council (EPSRC) Centre for Medical Engineering

Engineering and Physical Sciences Research Council Centre for Doctoral Training in Medical Imaging

National Institute of Health Research University College London Hospitals Biomedical Research Centre

United Kingdom Department of Health’s Research Centres funding scheme

Marvin Weil Epilepsy Research Fund and Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie

United Kingdom Epilepsy Society

Medical Research Council (United Kingdom) Clinician Scientist Fellowship

Neurodis Foundation

Publisher

Oxford University Press (OUP)

Subject

General Earth and Planetary Sciences,General Environmental Science

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