Altered Subcellular Distribution of the 75‐ kD a DISC 1 Isoform, cAMP Accumulation, and Decreased Neuronal Migration in Schizophrenia and Bipolar Disorder: Implications for Neurodevelopment

摘要

Summary Background DISC 1 (Disrupted‐In‐Schizophrenia‐1) is considered a genetic risk factor for schizophrenia ( SZ ) and bipolar disorder ( BD ). DISC 1 regulates microtubule stability, migration, and cAMP signaling in mammalian cell lines and mouse brain tissue. cAMP is a regulator of microtubule organization and migration in neurons. Aberrant microtubule organization has been observed in olfactory neuronal precursors ( ONP ) derived from patients with SZ and BD , which suggests involvement of DISC 1 and cAMP . However, the biology of DISC 1 in the physiopathology of psychiatric conditions remains elusive. Aims Herein, utilizing ONP obtained from SZ , BD patients and healthy subjects, we have studied DISC 1 expression, protein levels, and subcellular distribution by qRT ‐ PCR , immunoblotting, subcellular fractionation, and confocal microscopy. Cell migration and cAMP accumulation were assessed by Transwell and PKA competition assays. Results We found increased levels of the 75‐ kD a DISC 1 isoform in total cell extracts of ONP from patients with SZ and BD compared with controls. Subcellular distribution showed a significant decrease of cytoplasmic DISC 1 concomitant with its augmented levels in transcription sites. Moreover, significant cAMP accumulation and diminished migration were also observed in patients' cells. Conclusion Alterations of DISC 1 levels and its cellular distribution, which negatively modify cAMP homeostasis, microtubule organization, and cell migration, in ONP from patients with SZ and BD , suggest that their presence in early stages of brain development may impact brain maturation and function.