Increased pituitary adenylate cyclase-activating peptide genes expression in the prefrontal cortex in schizophrenia in relation to suicide

Abstract

IntroductionPituitary adenylate cyclase-activating peptide (PACAP) is a stress-related neuropeptide that is produced in several brain areas. It acts by 3 receptors: PACAP type-1 (PAC1), vasoactive intestinal peptide (VIP) -1 and -2 (VPAC1 and 2). Data on polymorphisms in PACAP and PAC1 indicate a relationship of the PACAP system with schizophrenia (SCZ).MethodsThe prefrontal cortex was chosen to measure PACAP-gene related expression changes, since this is a central structure in the symptoms of schizophrenia (SCZ). We investigated alterations in the expression of the PACAP-related genes by qPCR in the human dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of 35 SCZ patients and 34 matched controls in relation to SCZ, suicide, gender and medication.ResultsThe ACC revealed an upregulation in PACAP, PAC1, VPAC1 and VPAC2 in SCZ suicide (S) completers compared to controls. An increase in PACAP, VPAC1 and VPAC2 expression was also present in the ACC in SCZ-S compared to SCZ patients who died naturally (SCZ-N). In the DLPFC, an increase in PAC1 was found in SCZ-N patients compared to SCZ-S and controls. Moreover, an increase in all PACAP-related genes was present in SCZ-N male patients compared to SCZ-N females. Concluding, expression changes were found in PACAP-related genes in relation to SCZ, suicide and gender. In particular, there was a higher PACAP-related gene expression in SCZ patients in the ACC in relation to suicide and in DLPFC in relation to SCZ.DiscussionThese findings suggest a potential link between PACAP and the pathophysiology of SCZ and suicide. Further research is needed to understand the functional significance and potential clinical applications of these changes.

Alterations in pituitary adenylate cyclase-activating polypeptide in major depressive disorder, bipolar disorder, and comorbid depression in Alzheimer's disease in the human hypothalamus and prefrontal cortex

“…However, it should be noted that there are conditions, such as BD, where a little lower CSF pH is not considered a confounding factor, but rather an endophenotype of this disorder (Dogan, Yuksel, Du, Chouinard, & Öngür, 2018;Hagihara et al, 2018;Slabe et al, 2023). This phenomenon was also observed in the present study, and is due to increased lactate levels (Dogan et al, 2018;Hagihara et al, 2018).…”

“…Brain pH is also associated with changes in gene expression, and therefore presents a potential biomarker that should be examined further in relation to neuropsychiatric disorders (Dogan et al, 2018;Slabe et al, 2023). We observed a positive correlation between the mRNA expression between PACAP, VPAC1 and VPAC2 and CSF pH in the ACC of BD patients, and between PACAP-mRNA and pH in the ACC of BD-P patients.…”

“…mRNA Changes in PACAP and receptor genes in BD and MDD in suicide We found an increased PACAP-mRNA expression in the ACC in both BD and MDD patients with accomplished suicide, as compared to mood disorder patients who died from natural causes. Interestingly, in an earlier study we found an increased mRNA expression of PACAP, VPAC1 and VPAC2 in the ACC of schizophrenia patients who completed suicide as compared to schizophrenic patients who died from natural causes (Slabe et al, 2023). This means that the increased mRNA expression of PACAP in relation to suicide is independent of the underlying neuropsychiatric disorder.…”