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Disrupted-In-Schizophrenia 1 (DISC1), a risk factor for major mental illnesses, has been studied extensively in the context of neurodevelopment. However, the role of DISC1 in neuronal signaling, particularly in conjunction with intracellular cascades that occur in response to dopamine, a neurotransmitter implicated in numerous psychiatric disorders, remains elusive. Previous data suggest that DISC1 interacts with numerous proteins that impact neuronal function, including activating transcription factor 4 (ATF4). In this study, we identify a novel DISC1 and ATF4 binding region in the genomic locus of phosphodiesterase 4D (PDE4D), a gene implicated in psychiatric disorders. We found that the loss of function of either DISC1 or ATF4 increases PDE4D9 transcription, and that the association of DISC1 with the PDE4D9 locus requires ATF4. We also show that PDE4D9 is increased by D1-type dopamine receptor dopaminergic stimulation. We demonstrate that the mechanism for this increase is due to DISC1 dissociation from the PDE4D locus in mouse brain. We further characterize the interaction of DISC1 with ATF4 to show that it is regulated via protein kinase A-mediated phosphorylation of DISC1 serine-58. Our results suggest that the release of DISC1-mediated transcriptional repression of PDE4D9 acts as feedback inhibition to regulate dopaminergic signaling. Furthermore, as DISC1 loss-of-function leads to a specific increase in PDE4D9, PDE4D9 itself may represent an attractive target for therapeutic approaches in psychiatric disorders.

DISC1–ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1