News Releases & Research Results Discovery of the molecular and neural mechanisms involved in the refractory manifestations of schizophrenia: Elucidation of a novel function of the schizophrenia-related gene SETD1A

The results of the research and development project conducted by Researcher Kenichiro Nagahama (at the time of research), Assistant Professor Naofumi Uesaka (at the time of research), Professor Masanobu Kano of the Department of Neurophysiology, Graduate School of Medicine of the University of Tokyo, and others.

• De novo mutations of the human gene SETD1A* are known to be closely related to the onset of schizophrenia. The research group generated mice carrying the equivalent mutation of human SETD1A (i.e., mutation of murine Setd1a) and analyzed them. The results showed that the disruption of Setd1a impairs the neural circuits in the prefrontal cortex and causes schizophrenia-related behavioral abnormalities.
  *SETD1A is a gene encoding histone 3 lysine 4 methyltransferase. This enzyme is located in the cell nucleus, and it catalyzes the chemical reaction that methylates the histone, the chief protein components of chromatin.
• Specifically, Setd1a-mutant mice exhibited altered gene expression and attenuated excitatory synaptic transmission in the prefrontal cortex as well as various behavioral abnormalities relevant to the manifestations of schizophrenia. These results suggest that abnormalities in SETD1A, which controls the excitatory synaptic function in the human prefrontal cortex, may contribute to the pathophysiology of schizophrenia.
• The results of this R&D project should facilitate the elucidation of the pathogenesis of schizophrenia and the development of new therapeutic modalities for treatment.

This research project was conducted with the support of the Brain Mapping by Integrated Neurotechnologies for Disease Studies by AMED.

The results of this R&D project were published in Cell Reports on September 16.

Nagahama K., et al. Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities Cell Reports
DOI：10.1016/j.celrep.2020.108126