Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?
| Autor: | Linus De Witte, Kinga Gawel, Nancy Saana Banono, Camila V. Esguerra |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Psychosis Heterozygote Reflex Startle Time Factors Calcium Channels L-Type Genotype Neuroscience (miscellaneous) Context (language use) Motor Activity Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Neurobehaviour medicine Animals Zebrafish Alleles Genetics Thigmotaxis Splice site mutation biology Behavior Animal Prepulse Inhibition Wild type Heterozygote advantage Electroencephalography Darkness Zebrafish Proteins medicine.disease biology.organism_classification Disease Models Animal CACNA1D 030104 developmental biology Neurology Larva Mutation Schizophrenia RNA Splice Sites Haploinsufficiency 030217 neurology & neurosurgery Neuropsychiatric disorders |
| Zdroj: | Molecular Neurobiology |
| ISSN: | 1559-1182 0893-7648 |
| Popis: | Persons with certain single nucleotide polymorphisms (SNPs) in theCACNA1Dgene (encoding voltage-gated calcium channel subunit alpha 1-D) have increased risk of developing neuropsychiatric disorders such as bipolar, schizophrenia and autism. The molecular consequences of SNPs on gene expression and protein function are not well understood. Thus, the use of animal models to determine genotype-phenotype correlations is critical to understanding disease pathogenesis. Here, we describe the behavioural changes in larval zebrafish carrying an essential splice site mutation (sa17298) incacna1da. Heterozygous mutation resulted in 50% reduction of splice variants 201 and 202 (haploinsufficiency), while homozygosity increased transcript levels of variant 201 above wild type (WT; gain-of-function, GOF). Due to low homozygote viability, we focused primarily on performing the phenotypic analysis on heterozygotes. Indeed,cacna1dasa17298/WTlarvae displayed hyperlocomotion—a behaviour characterised in zebrafish as a surrogate phenotype for epilepsy, anxiety or psychosis-like behaviour. Follow-up tests ruled out anxiety or seizures, however, as neither thigmotaxis defects nor epileptiform-like discharges in larval brains were observed. We therefore focused on testing for potential “psychosis-like” behaviour by assayingcacna1dasa17298/WTlarval locomotor activity under constant light, during light-dark transition and in startle response to dark flashes. Furthermore, exposure of larvae to the antipsychotics, risperidone and haloperidol reversedcacna1da-induced hyperactivity to WT levels while valproate decreased but did not reverse hyperactivity. Together, these findings demonstrate thatcacna1dahaploinsufficiency induces behaviours in larval zebrafish analogous to those observed in rodent models of psychosis. Future studies on homozygous mutants will determine howcacna1dGOF alters behaviour in this context. |
| Databáze: | OpenAIRE |
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