GABA-A receptor differences in schizophrenia: a positron emission tomography study using [C-11]Ro154513
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case–control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [11C]Ro15-4513 VT and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.
Date Issued
2020-04-15
Date Acceptance
2020-03-04
Citation
Molecular Psychiatry, 2020, 26, pp.2616-2625
ISSN
1359-4184
Publisher
Springer Nature [academic journals on nature.com]
Start Page
2616
End Page
2625
Journal / Book Title
Molecular Psychiatry
Volume
26
Copyright Statement
© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
License URL
Sponsor
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000526337600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
G1002226
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Neurosciences
Psychiatry
Neurosciences & Neurology
ALPHA-5 SUBUNIT
IN-VIVO
BENZODIAZEPINE-RECEPTOR
TONIC INHIBITION
PREFRONTAL CORTEX
DOPAMINE SYSTEM
BINDING
EXPRESSION
PET
HIPPOCAMPUS
Publication Status
Published
Date Publish Online
2020-04-15