Purinergic System Transcript Changes in the Dorsolateral Prefrontal Cortex in Suicide and Major Depressive Disorder

Suicide is a major public health priority, and its molecular mechanisms appear to be related to imbalanced purine metabolism in the brain. This exploratory study investigates purinergic gene expression in the postmortem dorsolateral prefrontal cortex (DLPFC) tissue isolated from subjects with major depressive disorder (MDD) who died by suicide (MDD-S, n = 10), MDD subjects who did not die by suicide (MDD-NS, n = 6) and non-psychiatrically ill controls (CTL, n = 9-10). Purinergic system transcripts were assayed by quantitative polymerase chain reactions (qPCR) in superficial and deep gray matter as well as white matter DLPFC cortical layers using laser microdissection (LMD). Across all subjects, regardless of sex, P2RY12 (F_(2,23) = 5.40, p = 0.004) and P2RY13 (KW statistic = 11.82, p = 0.001) transcript levels were significantly greater in MDD-S compared to MDD-NS subjects. Several other perturbations were observed in the white matter tissue isolated from females: NT5E (F_(2,10) = 13.37, p = 0.001) and P2RY13 (F_(2,9) = 3.99, p = 0.011, controlled for age) transcript expression was significantly greater in MDD-S vs. MDD-NS female groups. ENTPD2 (F_(2,10) = 5.20, p = 0.03), ENTPD3 (F_(2,10) = 28.99, p < 0.0001), and NT5E (F_(2,10) = 13.37, p = 0.001) were among the transcripts whose expression was significantly elevated in MDD-S vs. CTL female groups. Transcripts that exhibited significantly altered expression in the superficial and deep gray matter included ENTPD2, NT5E, PANX1, and P2RY13 (p ≤ 0.05). Our medication analysis revealed that the expression of these transcripts was not significantly altered by antidepressants. This is the first study to holistically quantify the purinergic metabolic pathway transcripts in suicide and MDD utilizing human postmortem brain tissue. Our preliminary findings support evidence implicating changes in purinergic P2 receptors in the brain in suicide and provide support for broader purinergic system dysregulation in mood disorders.