A study in the journal Molecular Psychiatry reveals the molecular mechanisms to explain how theYWHAZgene, which is linked to psychiatric and neurological disorders such as autism and schizophrenia, can alter the neurodevelopmental process.
The group, which uses a zebrafish as an animal model, is led by Noelia Fernandez-Castillo and Bru Cormand, members of the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB), the Sant Joan de Deu Research Institute (IRSJD), and the Rare Diseases Networking Biomedical Centre (CIBERER), and William H. J. Norton of the University of Leicester (United Kingdom). Among the other collaborators
YWHAZgene and neurodevelopment
TheYWHAZgene has codified the 14-3-3 protein, a member of a family of highly conserved proteins that are expressed in the central nervous system. This gene, which is located in the chromosome 8 in humans, is mainly related to neuron formation, differencing, and positioning during neurodevelopment, mostly in experiments conducted on murine models.
The starting point for this study is a massive sequencing study (Molecular Pyschiatry,2013) on autism''s genetic bases, in which a mutation in the YWHAZ gene was discovered in two affected siblings. The new study model is the zebrafish (Danio rerio), a good model for learning behavioral changes related to autism and other psychiatric disorders, according to lecturer Noelia Fernandez-Castillo from the Department of Genetics, Microbiology, and
Unlike animal models, the larvae are transparent and small she continues to work, allowing us to evaluate the neuronal activity of the brain in vivo, which we cannot do for other animals. We have a transgenic line of the zebrafish in which all neurons express a marker that turns fluorescent when the neuron activates. This is how we can better understand what happens to animals with deficiencies in theywhazgene and to those in a control group.
The animal models whose gene has been deactivated have an altered hindbrain connectivity during larval stages, and a decreased collective neuronal activity, according to a research. This would likely be the result of the shortcomings in the neurotransmission observed in adult animals, which may result in behavioral changes in response to novelty. In fact, neurotransmission variations have been described in disorders such as autism, ADHD, and schizophrenia, according to a researcher at the UB and ICREA Academia 2021.
Besides, previous findings on animal models showed that the spontaneous collective neuronal activity is essential for development, as it is involved in the configuration of future neuronal networks, according to Ester Anton-Galindo, the first author of the article and Elisa Dalla Vechia (University of Leicester). The alteration of the spontaneous activity observed in animals with theywhazgene deactivated since early stages (larval) would result in inadequate development of neuronal connections and networks, according to the researcher.
Finding new therapeutic treatments
Key neurotransmitter alterations are also identified in behaviour, such as dopamine and serotonin. Behavioral alterations are re-established when administering drugs that affect these neurotransmission systems, which are similar to those of normal fish. This study enables us to understand the mechanisms through which this gene influences autism, which is a neurodevelopmental disorder, according to researcher Noelia Fernandez-Castillo.
According to Cormand, the use of two medications that modulate neurotransmission fluoxetine and quinpirole can significantly reduce alterations of the social behavior that present the mutant fish. This is good news, because fluoxetine is already used in humans in order to treat other pathologies, such as depression, and even some symptoms of autism, such as repetitive behaviors.
Despite its origin in the chromosome 19 of the zebrafish, it is expressed in the brain during the embryonic development (neurogenesis, neuronal differentiation, etc.). However, it has an expression restricted to certain areas of the brain in adult individuals, including the Purkinje cells, a type of neurons in the cerebellum that are reduced in number and size in individuals with autism. Therefore, the results indicate that these traits are identical.
The new study, in the field of clinical research, has added a new gene to the dozens and hundreds of genes related to the autism spectrum disorder. However, we need further research to define the genetic landscape, also known as all the responsible genes. When this landscape is completed, we may begin using genetic-based diagnostic tools to obtain the clinical diagnosis. According to Cormand,
Zebrafish: male and female differences
YWHAZ-gene-deficient females are considered to be more attractive when it comes to comparing results of similarly deficient males to those found in control groups. However, these differences were not that significant when it comes to comparing social behaviour.
Although experimental studies with the zebrafish model tend to involve both sexes mixed, this study demonstrates the importance of being mindful of the sex of the animal in animal experiments. Fernandez-Castillo claims that prior experiments in rats and mice had not been conducted on females, nor did possible differences be determined due to the gender.
"He continues to maintain that, although policies that encompass the gender perspective are influencing to modify these practices, thus allowing us to obtain a broader knowledge that may be applied to clinical practice in men and women in a greater way.
Innovative techniques for evaluating autism''s genetics
Thanks to a collaboration with the Institute of Photonic Sciences, the use of innovative techniques combined with in vivo monitoring techniques of the neuronal activity is critical to better understanding the mechanisms involved in autism.
"Although the CRISPR technique allows for gene editing, it is possible to obtain gene-deficient fish in a relatively quick and convenient way. "The whole brain imaging technique allows us to study in vivo the activity of all neurons in the brain individually, which is not possible with other techniques or animal models, and to improve our understanding of neural circuits during the development and their affectation in psychiatric disorders," said the researcher.
According to UB Professor Jordi Garcia-Fernandez, theywhazgene in zebrafish is the orthologue of theYWHAZgene in humans (i.e., they have a common ancestor and have separated through a process of speciation), so that this gene has not been replicated in the genome of teleosts the group to which zebrafish belong has allowed it to useywhazdeficiency in zebrafish as a model to
For the 2014-2020 period, the Spanish Ministry of Science, Innovation, and Universities provided funding for the study.