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Role of the PACAP-PAC1-DISC1 and PACAP-PAC1-stathmin1 systems in schizophrenia and bipolar disorder: novel treatment mechanisms?

Two pituitary adenylate cyclase-activating polypeptide (PACAP)-signaling pathways linked to schizophrenia were reviewed. One pathway regulates the association between disrupted-in-schizophrenia 1 (DISC1) and DISC1-binding zinc-finger protein via PACAP, and the other inhibits stathmin1 expression via PACAP. PACAP reduces the association of the binding between DISC1 (a potential susceptibility gene for major psychiatric disease) and DISC1-binding zinc-finger protein (which binds to DISC1 near the translocation site) to induce neurite outgrowth. In addition, an association between SNPs of the PACAP or PAC1 genes and schizophrenia has been reported. On the other hand, expression of stathmin1, which induces abnormal axonal arborization, is upregulated in PACAP-knock out mice and the brains of patients with schizophrenia. Thus it is likely that, in the schizophrenic brain, the neural development depending on these two systems has been disturbed. The possibility that the regulation of these two systems could lead to new treatments for schizophrenia is also discussed.