Cargando…

Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1

PURPOSE: The human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZ...

Descripción completa

Detalles Bibliográficos
Autores principales: Xie, Jiaheng, Jusuf, Patricia R., Bui, Bang V., Dudczig, Stefanie, Sztal, Tamar E., Goodbourn, Patrick T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991922/
https://www.ncbi.nlm.nih.gov/pubmed/33749720
http://dx.doi.org/10.1167/iovs.62.3.29
_version_ 1783669271813947392
author Xie, Jiaheng
Jusuf, Patricia R.
Bui, Bang V.
Dudczig, Stefanie
Sztal, Tamar E.
Goodbourn, Patrick T.
author_facet Xie, Jiaheng
Jusuf, Patricia R.
Bui, Bang V.
Dudczig, Stefanie
Sztal, Tamar E.
Goodbourn, Patrick T.
author_sort Xie, Jiaheng
collection PubMed
description PURPOSE: The human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including postsynaptic density 95 (PSD-95), N-methyl-d-aspartate receptors (NMDARs), corticotropin-releasing factor receptor 1 (CRFR1), and serotonin 2A receptors. The purpose of the present study was to elucidate the role of PDZK1. METHODS: We generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioral and functional levels using the optomotor response and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1, and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks, and 8 weeks of age. Standard RT-PCR and nonsense-mediated decay interference treatment were also performed to assess genetic compensation in mutants. RESULTS: Relative to wild-type, pdzk1-KO larvae showed spatial frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). No synaptic phenotypes, but possible morphological retinal phenotypes, were identified. We confirmed that the absence of major histological phenotypes was not attributable to genetic compensatory mechanisms. CONCLUSIONS: Our findings point to a role for pdzk1 in zebrafish visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behavior.
format Online
Article
Text
id pubmed-7991922
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher The Association for Research in Vision and Ophthalmology
record_format MEDLINE/PubMed
spelling pubmed-79919222021-03-30 Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1 Xie, Jiaheng Jusuf, Patricia R. Bui, Bang V. Dudczig, Stefanie Sztal, Tamar E. Goodbourn, Patrick T. Invest Ophthalmol Vis Sci Visual Neuroscience PURPOSE: The human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including postsynaptic density 95 (PSD-95), N-methyl-d-aspartate receptors (NMDARs), corticotropin-releasing factor receptor 1 (CRFR1), and serotonin 2A receptors. The purpose of the present study was to elucidate the role of PDZK1. METHODS: We generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioral and functional levels using the optomotor response and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1, and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks, and 8 weeks of age. Standard RT-PCR and nonsense-mediated decay interference treatment were also performed to assess genetic compensation in mutants. RESULTS: Relative to wild-type, pdzk1-KO larvae showed spatial frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). No synaptic phenotypes, but possible morphological retinal phenotypes, were identified. We confirmed that the absence of major histological phenotypes was not attributable to genetic compensatory mechanisms. CONCLUSIONS: Our findings point to a role for pdzk1 in zebrafish visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behavior. The Association for Research in Vision and Ophthalmology 2021-03-22 /pmc/articles/PMC7991922/ /pubmed/33749720 http://dx.doi.org/10.1167/iovs.62.3.29 Text en Copyright 2021 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Visual Neuroscience
Xie, Jiaheng
Jusuf, Patricia R.
Bui, Bang V.
Dudczig, Stefanie
Sztal, Tamar E.
Goodbourn, Patrick T.
Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1
title Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1
title_full Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1
title_fullStr Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1
title_full_unstemmed Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1
title_short Altered Visual Function in a Larval Zebrafish Knockout of Neurodevelopmental Risk Gene pdzk1
title_sort altered visual function in a larval zebrafish knockout of neurodevelopmental risk gene pdzk1
topic Visual Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991922/
https://www.ncbi.nlm.nih.gov/pubmed/33749720
http://dx.doi.org/10.1167/iovs.62.3.29
work_keys_str_mv AT xiejiaheng alteredvisualfunctioninalarvalzebrafishknockoutofneurodevelopmentalriskgenepdzk1
AT jusufpatriciar alteredvisualfunctioninalarvalzebrafishknockoutofneurodevelopmentalriskgenepdzk1
AT buibangv alteredvisualfunctioninalarvalzebrafishknockoutofneurodevelopmentalriskgenepdzk1
AT dudczigstefanie alteredvisualfunctioninalarvalzebrafishknockoutofneurodevelopmentalriskgenepdzk1
AT sztaltamare alteredvisualfunctioninalarvalzebrafishknockoutofneurodevelopmentalriskgenepdzk1
AT goodbournpatrickt alteredvisualfunctioninalarvalzebrafishknockoutofneurodevelopmentalriskgenepdzk1