Schizophrenia is a chronic psychiatric disorder characterized by continuous or relapsing episodes of psychosis that can alter severely normal brain function. This mental health issue makes it arduous to determine what is real or not, producing symptoms such as hallucinations, delusions, and disorganized thinking. Therefore, this illness is a serious mental disorder that affects around 1 to 300 people, meaning 24 million people globally.
Although there is treatment available, there is still not a definitive cure for schizophrenia, despite the excruciating efforts employed in research. Current research includes the use of zebrafish, and scientists hope this alternative model will be able to accelerate basic research and Drug Discovery for this disabling condition.
What is schizophrenia?
This mental illness causes psychotic events that affect how a person thinks and behaves, losing control of its thoughts and actions. These unstable events are not continuous and may cause hallucinations, usually involving hearing and delusions, which are characterized by a distortion in self-experience causing bizarre or persecutory feelings. These events can produce thought-blocking and disorganized speech, so they are immensely disabling; fortunately, they usually respond well to medication.
The first symptoms usually appear in young adults o, although positive symptoms, produced by psychotic events, respond well to the medication, there are others that appear in the non-psychotic phase. These symptoms are characterized by deficits of normal emotional response or thought processes that include loss of emotions, diminish speech capabilities, inability to feel pleasure, and lack of motivation.
What causes schizophrenia?
Research shows that schizophrenia is caused by a dysfunction in the brain caused by several factors, including genetic and environmental components. According to genetic factors, only a small number of genetic variants are related to the disease, and each has a small impact on the likelihood of suffering from this disorder. Nevertheless, genetics has been related to pathology as the main risk factor for developing schizophrenia, having a first-degree relative with this illness is considered a major factor for predisposition. Each genetic variant can contribute to an extent of the disease and in addition to the environmental factors, this could be the explanation for the cause of the disease. Among environmental factors, being raised in cities, childhood adversities, cannabis consumption, infections, or poor nutrition during pregnancy are the most relevant factors that may act with genetics to develop the pathology.
The role of Zebrafish in schizophrenia research
The availability of good animal disease models is extremely important for advancing into physiological and molecular basis. Regarding psychiatric disorders, lots of basic and translational research is necessary to advance into the biological mechanisms of these illnesses. Unfortunately, there are no good models since these diseases are complex, we cannot classify them correctly and their neuro-physiological effects remain elusive. For schizophrenia, some models are available replicating some of the conditions seen in patients. Traditionally, rodents have been used for neurological medical research, but they are costly, time-consuming, and involve ethical issues.
In this sense, the Zebrafish is proving to be a valuable New Alternative Model (NAM) in the study of schizophrenia. This tiny tropical fish can make decisions and process thoughts in a similar way to humans, and it has a similar genetic makeup to humans (approximately 70%), in particular the brain structure, including all the different neuronal subtypes, and the Blood Brain Barrier (BBB). Actually, there is a pharmacological model of schizophrenia induced by MK-801, that has been used to mimic the schizophrenia behavior in zebrafish and screen the efficacy of compounds against it, as well as other mutants of dopaminergic transporters, solving easily the problem of not having disease models in animals for several neuronal diseases.
Other advantages in the study of schizophrenia are the rapid breeding and cost-efficiency of zebrafish. They create several hundred embryos every few days and are cost-effective to breed due to their small size. Besides, this small size allows High Content Screenings (HCS) enabling the testing of hundreds of compounds in an affordable manner. This allows scientists to study different aspects of psychological and cognitive behavior and schizophrenia evolution, brain cells react to Drug therapies in a much more time and cost-efficient way than with rodents.
The zebrafish embryo is transparent and develops outside the uterus, making it a suitable candidate for external observation of testing materials. From the moment a single brain cell develops, and brain activity begins, through to full formation, its transparency facilitates the study of this the brain neuronal types in this alternative model.
The zebrafish brain develops fast, forming within 96 hours of fertilization (hpf), and within 120 hpf it can show behavior related to psychiatric disorders. This allows developing behavioral studies in embryos with less than 6 days post fertilization (dpf). At this stage, the larvae are considered experimental animals but they are among the NAM that fulfills highly ethical standards in alignment with the 3Rs Principles: Reduction, Refinement, and Replacement. This internationally recognized policy seeks to follow more humane animal research methods by:
- Reducing testing on animals
- Minimizing suffering and distress inflicted on animals during research
- Avoiding testing on animals where possible
While it is understood that some testing on animals is necessary for medical science to advance in the treatment and prevention of human diseases and well-being, the 3Rs highlight the importance of using an alternative model whenever possible.
With this philosophy, Biobide has implemented the use of the Zebrafish larvae (less than 6 dpf) model for the study of neurological disorders and Drug toxicity for the Neurotox Assay. This assay is a High Content Screening (HCS) assay that evaluates automatically different neurological patterns based on the swimming behavior of the larvae. Thus, these swimming patterns show the neurological effect of a compound showing hyper- or hypoactivity, anxiety, absence of movement (sleeping), or habituation to a stimulus. Therefore, Biobide’s Neurotox Assay offers the capacity of testing hundreds of compounds fast, in a cost-effective manner, and with fewer ethical concerns, to discharge compounds with neurotoxicity in early stages of the Drug Discovery & Developmental process.
Conclusion
Schizophrenia is a major health concern, and it is a severe chronic psychiatric pathology affecting millions of people worldwide that impacts strongly the quality of life and life expectancy of patients. Therefore, there is an urgent need for advancing the comprehension of the physiological basis of the disease for developing more effective treatments.
For this matter, the use of animal models in basic research and the Drug Discovery process is tremendously relevant for advancing the knowledge and treatments of diseases. However, the use of mammalian animal models is costly, time-consuming, and presents ethical concerns. In this sense, NAMs have been proposed to overcome this situation and the zebrafish have proven as a useful and cost-effective alternative, especially, using larvae of less than 6 dpf.
Using zebrafish, scientists can study how the brain forms and what causes specific cells to mutate and cause schizophrenia. This is especially relevant for research into what is la leading cause of genetically inherited schizophrenia, due to the zebrafish’s similarity to the human genome and the Drug Discovery process, due to the possibility of developing HCS assays in a cost-effective manner.
Sources
- https://www.nimh.nih.gov/health/topics/schizophrenia
- https://www.psychiatry.org/patients-families/schizophrenia/what-is-schizophrenia
- https://www.who.int/news-room/fact-sheets/detail/schizophrenia
- https://www.sciencedirect.com/science/article/abs/pii/S0149763419300892#:~:text=Zebrafish%20(Danio%20rerio)%20is%20emerging,valuable%20animal%20model%20of%20schizophrenia.&text=Although%20pharmacological%20models%20of%20schizophrenia,further%20validation%20is%20still%20required
- A critical review of zebrafish schizophrenia models: Time for validation? Kinga Gawel et al. 2019
- Abnormal Behavior of Zebrafish Mutant in Dopamine Transporter Is Rescued by Clozapine, iScience, Volume 17, 2019, pp. 325-333
