Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia

Abstract

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.

Keywords: adenosine receptors; anterior cingulate cortex; neuromodulation; pyramidal neurons; schizophrenia; transcript expression.

Figure 1

Adenosine A₁ receptor (A₁R) and A_2A receptor (A_2AR) mRNA expression in an enriched population of anterior cingulate cortex (ACC) pyramidal neurons in control (CTL) vs. schizophrenia (SCZ) subjects. (A) A₁R and (B) A_2AR mRNA expression was not significantly different between SCZ and CTL subjects. n = 18–19/group. Open circles indicate female subjects and closed circles indicate male subjects. Data are presented as means.

Figure 2

Adenosine A₁ receptor (A₁R) and A_2A receptor (A_2AR) mRNA expression in an enriched population of anterior cingulate cortex (ACC) pyramidal neurons in female control (CTL) vs. schizophrenia (SCZ) subjects and male CTL vs. SCZ subjects. (A) A₁R mRNA expression was significantly increased in female SCZ subjects compared to female CTL subjects. (B) A_2AR mRNA expression was not significantly different between female SCZ subjects and female CTL subjects. (C) A₁R mRNA expression and (D) A_2AR mRNA expression were not significantly different between male SCZ subjects and male CTL subjects. n = 7–12/group. Open circles indicate female subjects and closed circles indicate male subjects. Data are presented as means. * p < 0.05.

Figure 3

Adenosine A₁ receptor (A₁R) and A_2A receptor (A_2AR) mRNA expression in an enriched population of anterior cingulate cortex (ACC) pyramidal neurons in control (CTL) female vs. male subjects and female vs. male schizophrenia (SCZ) subjects. (A) A₁R mRNA expression was significantly decreased in female CTL subjects compared to male CTL subjects. (B) A_2AR mRNA expression was not significantly different between female CTL subjects and male CTL subjects. (C) A₁R mRNA expression and (D) A_2AR mRNA expression were not significantly different between female SCZ subjects and male SCZ subjects. n = 7–12/group. Open circles indicate female subjects and closed circles indicate male subjects. Data are presented as means. * p < 0.05.

Figure 4

Adenosine A₁ receptor (A₁R) and A_2A receptor (A_2AR) mRNA expression in an enriched population of anterior cingulate cortex (ACC) pyramidal neurons in control (CTL) and schizophrenia (SCZ) subjects, binned according to clinical dementia rating (CDR) score. (A) A₁R mRNA expression was not significantly different across CDR bins. (B) A_2AR mRNA expression was significantly increased in subjects in the “very mild–mild” and “moderate–severe” bins compared to subjects with no dementia symptoms (“none” bin). n = 11–14/group. Open circles indicate female subjects and closed circles indicate male subjects. Data are presented as means. * p < 0.05.

Figure 5

Spearman’s correlation analysis between adenosine A₁ receptor (A₁R) and A_2A receptor (A_2AR) mRNA expression and clinical dementia rating (CDR) scores in control (CTL) and schizophrenia (SCZ) subjects. (A) No significant associations were observed between A₁R mRNA expression and CDR scores. (B) A significant, positive association was observed between A_2AR mRNA expression and CDR scores. CDR scores: 0 = no dementia, 0.5–1 = very mild to mild dementia, 2–3 = moderate to severe dementia. n = 37. Open squares indicate SCZ subjects and closed squares indicate CTL subjects. * p < 0.05.

Figure 6

Adenosine A₁ receptor (A₁R) and A_2A receptor (A_2AR) expression in an enriched population of anterior cingulate cortex (ACC) pyramidal neurons in schizophrenia (SCZ) subjects off vs. on antipsychotic medication. (A) A₁R mRNA expression was not significantly different between SCZ subjects on antipsychotic medication and SCZ subjects off antipsychotic medication. (B) A_2AR mRNA expression was significantly decreased in SCZ subjects on antipsychotic medication compared to SCZ subjects off antipsychotic medication. n = 5–12/group. Open circles indicate female subjects and closed circles indicate male subjects. Data are presented as means. * p < 0.05.