Studies on the Novel Role of Disrupted-in-schizophrenia 1 (DISC1) as a Transcriptional Regulator of Dopamine D1 Receptor (D1R) Expression

Abstract

Disrupted-in-Schizophrenia 1 (DISC1) is a scaffold protein implicated in various psychiatric diseases. Dysregulation of the dopamine system has been associated with DISC1-deficiency, while the molecular mechanism is unclear. In this study, I propose a novel molecular mechanism underlying the transcriptional regulation of the dopamine D1 receptor (D1R) in the striatum via DISC1. I verified the increase in D1R at the transcriptional level in the striatum of DISC1-deficient mouse models and altered histone acetylation status at the D1r locus. I identified a functional interaction between DISC1 and Krüppel-like factor 16 (KLF16). KLF16 translocates DISC1 into the nucleus and forms a regulatory complex by recruiting SIN3A corepressor complexes to the D1r locus. Moreover, DISC1-deficient mice have altered D1R-mediated signaling in the striatum and exhibit hyperlocomotion in response to cocaine; the blockade of D1R suppresses these effects. Taken together, the results in this study suggest that nuclear DISC1 plays a critical role in the transcriptional regulation of D1R in the striatal neuron, providing a mechanistic link between DISC1 and dopamine-related psychiatric symptoms. ER and mitochondria communicate through physical contact sites called mitochondria-associated ER membrane (MAM). In the previous study, we have revealed that DISC1 modulates neuronal stress responses by affecting the Ca2+ transfer at the MAM. During the study, however, we had recognized the lack of appropriate imaging techniques to measure the direct Ca2+ transfer through MAM. In this study, I developed a MAM-targeted genetically induced calcium indicator (GECI) with a high spatiotemporal specificity to MAM. I designed a novel bimolecular GECI, named spGCaMP, and introduced spGCaMP to the microdomain between ER and mitochondria. MAM-spGCaMP immediately responds to Ca2+ release from the ER induced by IP3, which is simultaneous with Ca2+ elevation in the cytoplasm but prior to the Ca2+ accumulation in the mitochondrial matrix. I demonstrate that MAM-spGCaMP provides a practical means for functional studies of MAM.