Cell-subtype-specific Changes in Adenosine Pathways in Schizophrenia

Overview

Journal Neuropsychopharmacology

Date 2018 Feb 28

PMID 29483661

Citations 30

Authors

Sinead Marie ODonovan

Courtney Sullivan

Rachael Koene

Emily Devine

Kathryn Hasselfeld

Cassidy Lynn Moody

Robert Erne McCullumsmith

Affiliations

Soon will be listed here.

Abstract

Prior work in animal models implicates abnormalities of adenosine metabolism in astrocytes as a possible pathophysiological mechanism underlying the symptoms of schizophrenia. In the present study, we sought to reverse-translate these findings back to the human brain in schizophrenia, focusing on the following questions: (1) Which components of the adenosine system are dysregulated in schizophrenia, and (2) are these changes limited to astrocytes? To address these questions, we captured enriched populations of DLPFC pyramidal neurons and astrocytes from schizophrenia and control subjects using laser capture microdissection and assessed expression of adenosine system components using qPCR. Interestingly, we found changes in enriched populations of astrocytes and neurons spanning metabolic and catabolic pathways. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1) and ENTPD2 mRNA levels were significantly decreased (p < 0.05, n = 16 per group) in enriched populations of astrocytes; in pyramidal neurons equilibrative nucleoside transporter 1 (ENT1) and adenosine A receptor mRNA levels were significantly decreased, with an increase in adenosine deaminase (ADA) (p < 0.05, n = 16 per group). Rodent studies suggest that some of our findings (AR and ENTPD2) may be due to treatment with antipsychotics. Our findings suggest changes in expression of genes involved in regulating metabolism of ATP in enriched populations of astrocytes, leading to lower availability of substrates needed to generate adenosine. In pyramidal neurons, changes in ENT1 and ADA mRNA may suggest increased catabolism of adenosine. These results offer new insights into the cell-subtype-specific pathophysiology of the adenosine system in this illness.

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