The goal of this project is to investigate the functions of schizophrenia-associated genes using zebrafish as a model system. Large-scale genome-wide association studies have begun to uncover numerous candidate genes linked to schizophrenia. Yet it remains unclear how these genes function and how they contribute to the underlying molecular, cellular, developmental and behavioral processes disrupted in the disorder. Recent technological breakthroughs in zebrafish ? targeted genome editing, whole-brain activity imaging, brain atlas registration, behavioral profiling ? combined with the ease of studying large numbers of animals make it an ideal system for analyzing psychiatric disease genes. Preliminary studies led to the creation of zebrafish mutants for 96 schizophrenia-associated genes. Characterization of 59 of these mutants for altered brain anatomy and activity has revealed 27 mutants with phenotypical abnormalities. In particular, ZNF536, a schizophrenia-associated transcription factor, was found to be involved in the development of GABAergic inhibitory neurons in the forebrain and cerebellum as well as regulate locomotion. During the K99 phase, this project will complete the analysis of mutant brain anatomy. In addition, all mutants will be tested for behavioral abnormalities, including motor behaviors associated with schizophrenia, such as defective prepulse inhibition (Aim 1). In parallel, the developmental roles of ZNF536 will be studied to test the hypothesis that this transcription factor is responsible for the development of GABAergic neurons, and that its loss results in the de-inhibition of downstream circuits. To define the molecular mechanisms by which ZNF536 exerts its effects, ZNF536 target genes will be isolated (Aim 2). Similar in-depth characterization of other interesting genes will be undertaken in the R00 phase to discover additional pathways regulated by schizophrenia-associated genes. Understanding the molecular, cellular, developmental and behavioral processes regulated by schizophrenia- associated genes will provide the foundation to understand the causes of schizophrenia and develop new diagnostics and therapies.

Public Health Relevance

The pathways underlying schizophrenia, a debilitating disease affecting 1% of the population, are not clear. This study will help define the function of schizophrenia-associated genes in vertebrate neurodevelopment and behavior and thus improve our understanding of the causes of the condition and provide a foundation for the development of new schizophrenia therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Career Transition Award (K99)
Project #
1K99MH110603-01A1
Application #
9314015
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Desmond, Nancy L
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Escamilla, Christine Ochoa; Filonova, Irina; Walker, Angela K et al. (2017) Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 551:227-231