Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior

The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of gamma-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate gamma-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.

By the author/editor: Dries, Daniel R.; Zhu, Yi; Brooks, Mieu M.; Forero, Diego A.; Adachi, Megumi; Cenik, Basar; show more...; West, James M.; Han, Yu-Hong; Yu, Cong; Arbella, Jennife ...; Nordin, Annelie; Adolfsson, Rolf; Del-Favero, Jurg ...; Lu, Q. Richard; Callaerts, Patri ...; Birnbaum, Shari ...; Yu, Gang; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Psychiatry

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.