21.4 CELL-TYPE SPECIFIC ALTERATIONS IN ADENOSINE-GENERATING PATHWAYS IN SCHIZOPHRENIA. (9th April 2019)

• Record Type: Journal Article
• Authors: O'Donovan, Sinead; Bentea, Eduard; McCullumsmith, Robert
• Is Part Of: Schizophrenia bulletin. Volume 45(2019)Supplement 2
• Page Start: S124
• Page End: S125
• Publication Date: 2019-04-09
• Subjects: Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbz022.088
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: Background: Adenosine is a potent neuromodulator of glutamate and dopamine neurotransmission and abnormalities of adenosine metabolism are a possible pathophysiological mechanism postulated to underlie the signs and symptoms of schizophrenia. Extracellular adenosine is mainly generated in two ways. ATP is released into the extracellular space and converted to adenosine via a series of enzymatic steps. Alternatively, adenosine is directly released from cells via equilibrative nucleoside transporters (ENTs). Indirect generation of adenosine via conversion of ATP is more typical of glial cells, while direct adenosine release is more typical of neurons, although the enzymes required to generate adenosine and the ENT transporters are found in both cell types. The relative contributions of directly released and indirectly generated adenosine and whether its source is neuronal or astrocytic are not fully understood. Methods: To address these questions, we captured enriched populations of dorsolateral prefrontal cortex pyramidal neurons and astrocytes (n=1000 cells/subject) from schizophrenia (n=16) and control (n=16) subjects using Nissl stain coupled to laser capture microdissection and assessed gene expression of adenosine system components using real-time qPCR. To account for the chronic effects of antipsychotics in postmortem tissue, a control study with rats administered haloperidol-decanoate (28.5mg/kg) or vehicle (sesame oil) for 9 months was carried out. Significantly altered gene targets in postmortem tissue were also assayed in rodents. Results: In schizophrenia, our data suggests that diverse cell-subtype specific mechanisms may contribute to hypofunction of the adenosine metabolism cascade. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) and ENTPD2 mRNA levels were significantly decreased (Student's t-test, p<0.05) in astrocytes; in pyramidal neurons ENT1 and adenosine A1 receptor mRNA levels were significantly decreased, with an increase in adenosine deaminase (Student's t-test, p<0.05). Rodent studies suggest that some of our findings (A1R and ENTPD2) may be due to treatment with antipsychotics. Conclusions: Our findings suggest reduced metabolism of ATP in astrocytes, leading to lower availability of substrates needed to generate adenosine. In pyramidal neurons, changes in ENT1 and ADA suggest increased catabolism of adenosine. These results support hypofunction of adenosine neurotransmission in schizophrenia, offering new insights into the cell-subtype specific pathophysiology of the adenosine system in this illness.