Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia

Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine signaling via the ubiquitously expressed adenosine receptors; however, adenosine A₁ and A_2A receptor (A₁R and A_2AR) mRNA expression is poorly understood in specific cell subtypes in the frontal cortical brain regions implicated in this disorder. In this study, we assayed A₁R and A_2AR mRNA expression via qPCR in enriched populations of pyramidal neurons, which were isolated from postmortem anterior cingulate cortex (ACC) tissue from schizophrenia (n = 20) and control (n = 20) subjects using laser microdissection (LMD). A₁R expression was significantly increased in female schizophrenia subjects compared to female control subjects (t₍₁₃₎ = -4.008, p = 0.001). A₁R expression was also significantly decreased in female control subjects compared to male control subjects, suggesting sex differences in basal A₁R expression (t₍₁₇₎ = 2.137, p = 0.047). A significant, positive association was found between dementia severity (clinical dementia rating (CDR) scores) and A_2AR mRNA expression (Spearman's r = 0.424, p = 0.009). A_2AR mRNA expression was significantly increased in unmedicated schizophrenia subjects, suggesting that A_2AR expression may be normalized by chronic antipsychotic treatment (F_(1,14) = 9.259, p = 0.009). Together, these results provide novel insights into the neuronal expression of adenosine receptors in the ACC in schizophrenia and suggest that receptor expression changes may be sex-dependent and associated with cognitive decline in these subjects.