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Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish

Version 2 2022-07-07, 09:17
Version 1 2022-07-06, 07:54
journal contribution
posted on 2022-07-07, 09:17 authored by Ester Anton-Galindo, Elisa Dalla Vecchia, Javier G Orlandi, Gustavo Castro, Emilio J Gualda, Andrew MJ Young, Marc Guasch-Piqueras, Concepcio Arenas, Carlos Herrera-Ubeda, Jordi Garcia-Fernandez, Fernando Aguado, Pablo Loza-Alvarez, Bru Cormand, William HJ Norton, Noelia Fernandez-Castillo
Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.

History

Author affiliation

Department of Genetics and Genome Biology, University of Leicester

Version

  • AM (Accepted Manuscript)

Published in

Molecular Psychiatry

Publisher

Springer Nature

issn

1359-4184

eissn

1476-5578

Acceptance date

2022-04-12

Copyright date

2022

Available date

2022-11-02

Spatial coverage

England

Language

English