Adenosine Metabolism Pathway Alterations in Frontal Cortical Neurons in Schizophrenia

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia (<i>n</i> = 20) and sex- and age-matched control subjects without psychiatric illness (<i>n</i> = 20) was obtained from the Bronx-Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components-adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5'-nucleotidase (NT5E)-were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups (<i>p</i> > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann-Whitney U = 86; <i>p</i> < 0.05), a finding significantly driven by disease (t₍₁₇₎ = 3.289; <i>p <</i> 0.05). Correlation analyses also demonstrated significant associations (<i>n</i> = 12) between the expression of several adenosine pathway components (<i>p</i> < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the "mild" clinical dementia rating (CDR) bin compared with males in the "none" CDR bin (F_{(2, 13)} = 5.212; <i>p < 0.05</i>). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects (<i>p</i> > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia's pathology.