Schizophrenia’s core symptoms are commonly believed to be inherent to humans, yet neuroscientists use rodent models in research to increase our knowledge of the disease. The etiology of schizophrenia is not known and rodent models have proven to be a useful tool in attempting to piece together our understanding of the disorder. This enables the direct assessment of hypotheses, which is not possible in a clinical population. And more, rodent models offer the means for testing and developing treatments for schizophrenia.
Celinecelines, In Transition, 2008
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Schizophrenia is a complex human disorder that cost the Canadian economy an estimated 2.02 billion dollars in 20041. Schizophrenia is commonly characterized by disorganized thought and speech, hallucinations and delusions. It would seem that the use of animals in the study of a disorder, the diagnosis of which is inundated with symptoms that cannot be directly applied to animals, would be a ludicrous task. However, it is exactly this that many neuroscientists are undertaking. Although animal models have obvious limitations, they are used in the study of human disorders, and suggest interesting findings.
What is schizophrenia?
Schizophrenia has classically been described by positive, negative and cognitive symptoms2. The symptoms most commonly known to the general population are referred to as positive symptoms and include hallucinations, delusions and bizarre or disorganized behavior. The negative symptoms, on the other hand, include affective flattening (a decrease in the range of expressing emotions) and social withdrawal2. The cognitive symptoms are associated with disorganized thought and speech as well as deficits in certain forms of memory2. However, because the exact etiology of the disorder is not known, and specific neurobiological markers are unavailable, the diagnosis of schizophrenia is based purely on the symptoms manifested by the patient. It is clear that many of the symptoms could not possibly be replicated animals, as many of the core symptoms require the ability to communicate thoughts and experiences. However, some symptoms have been modeled (such as a decrease in social interaction and certain memory deficits) and this has allowed animals to be used in the investigation of the neurobiology of schizophrenia.
The etiology of schizophrenia
The role of dopamine, a major neurotransmitter in the brain, in the pathology and treatment of schizophrenia has been the subject of investigation for approximately 50 years. It was originally thought that dopamine hyperactivity was actually responsible for symptoms such as hallucinations and delusions3. This theory originated from and is supported by the efficacy of antipsychotic medication (e.g. haloperidol), which cause a decrease in dopamine levels. The effects of psychomotor stimulants (e.g. cocaine, amphetamine) yield an increase in dopamine levels. It was also demonstrated in the clinical population of schizophrenia that patients have a heightened response to stimulants such as amphetamine, resulting in an increase in dopamine transmission, when compared to a healthy control population4. Also, an increased response to psychomotor stimulants is a classic phenotype demonstrated in animal models, where rodents demonstrate an increase in dopamine levels when exposed to drugs such as amphetamine5. It is important to note that our understanding of schizophrenia is not limited to the dopamine theory. However, it is one of the longest standing theories and often applied to animal models.
It is currently believed that the etiology of schizophrenia is a complex interaction between genetics and environmental factors that influence the later onset of the disorder. This suggests that schizophrenia is actually a neurodevelopmental disorder, meaning that there is an aberration in normal neural development that occurs before the onset of the symptoms6. The role of genetics and environmental factors on the development of schizophrenia has been investigated by both clinical and epidemiological studies with schizophrenic patients and through the use of animal models. Clinical and epidemiological studies have provided incredibly insightful information. Genes and environmental risk factors may be involved in the development of schizophrenia. However, these studies can only allow us to draw correlations, not causal inferences. This is where animal models have proven to be useful: they allow us to directly address factors of interest and investigate the role they may play on development, the brain and behavior.
Using rodent models to help understand schizophrenia
Animal models investigate structural, chemical and molecular changes in the brain of rodents as well as any behavioral changes. Although many animal models are used to investigate the etiology of schizophrenia (for a complete list see5, only models investigating a known environmental risk factors will be discussed. Still, it is interesting to note that there have been some major advances and interesting discoveries using animals to investigate the genetics of the disorder7,8. These allow researchers to examine causal relationships between a gene or a particular environmental influence and the development of the brain, an area of research that is not possible in clinical or epidemiological research.
Rodent models of environmental risk factors
Various environmental risk factors have been investigated. Recently there has been a focus on environmental influences on early development (as early as prenatal exposure). Environmental factors include obstetric complications, infection, and even the age of the father at conception9. There has been strong support for the involvement of early exposure to infection, in particular, as an environmental risk factor for the later development of schizophrenia10. Exposure to infections such as influenza, Taxoplasma gondii, as well as genital and reproductive pathogens during pregnancy have all been identified as potential risk factors11. These findings have sparked interest in the development of an animal model of early exposure to infection to investigate its relevance to schizophrenia. In this line of research, researchers induce illnesses in rats or mice through the injection of different compounds. These compounds either mimic a viral infection or cause a bacterial infection11. This allows for the investigation of the role of illness in a controlled manner and to study the effect during a particular period in development either in the prenatal stages or early after birth11. Rats or mice are examined during development and into adulthood to look at structural, chemical and molecular changes in the brain, as well as certain behaviors that can be mimicked in rodents and are typical of the clinical population of schizophrenia.
Their results have indicated that adult rats or mice that are exposed early in development to infection show distinct brain and behavioral changes that are similar to the ones observed in schizophrenic patients11. For example, some models found that rats exposed to early infections displayed impaired social interaction patterns and that this deficit was ameliorated by antipsychotic drugs. Others have found an increased sensitivity to amphetamine11 in those rodents. Together, both findings support claims by the dopamine theory mentioned earlier.
Furthermore, these findings suggest that there are similarities between the rodent models and our current understanding of the etiology of schizophrenia. It is also promising that the models have been effective in alleviating deficits by the use of antipsychotic drugs, demonstrating the validity of such models. Although continued research is still needed to validate these models in relation to schizophrenia, the preliminary results provide valuable insight into the influence of early illness and alterations in normal development. Ultimately, it could aid in prevention and treatment.
Future directions for rodent models
The current rodent models are evolving in the right direction. The combination of different models may gradually provide a piece-by-piece understanding of schizophrenia, even though such models will never directly mimic the disorder. Many reviews have reflected on both the limitations and benefits of rodent models6,7,8,12. What is critical for the improvement in rodent models is a continued communication within the neuroscience community. Letting research from clinical neuroscience guide research in basic neuroscience and vice versa, is currently the most promising way to piece together the puzzle of schizophrenia.
References
1. Goeree, R., et al. « The Economic Burden of Schizophrenia in Canada in 2004. » Current Medical Research and Opinion 12 (2006): 2017-18.
2. Andreason, N.C., and S. Olsen. « Negative V Positive Schizophrenia. » Archives of General Psychiatry 39 (1982): 789-94.
3. Carlsson, A., and M. Lindqvist. « Effects of Chlorpromazine or Halperidol on Formation of 3-Methoxytrymine and Normetanephrine in Mouse Brain. » Acta Pharmacology et Toxicology 20 (1963): 140-44.
4. Laruelle, M., et al. « Increased Dopamine Transmission in Schizophrenia: Relationship to Illness Phases. » Society of Biological Psychiatry 46 (1999): 52-72.
5. Koenig, Jim. « Animal Models of Schizophrenia. » January 20, 2008. Schizophrenia Research Forum. January, 2008 <http://www.schizophreniaforum.org/res/models/animal_modelsTable.pdf>
6. Powell, Craig M., and Tsuyoshi Miyakawa. « Schizophrenia-Relevant Behavioral Testing in Rodent Models: A Uniquely Human Disorder? » Biological Psychiatry 59.12 (2006): 1198-207.
7. Rapoport, J.L., et al. « The Neurodevelopmental Model of Schizophrenia: Update 2005. » Molecular Psychiatry 10 (2005): 434-49.
8. Abbott, Alison. « Model Behaviour. » Nature 450 (2007): 6-7.
9. Messias, E.L., C.Y. Chen, and W.W. Eaton. « Epidemiology of Schizophrenia: Review of Findings and Myths. » The Psychiatric Clinics of North America 30.3 (2007): 323-38.
10. Brown, A.S. « The Risk for Schizophrenia from Childhood and Adult Infections. » The American Journal of Psychiatry 165.1 (2008): 7-10.
11. Nawa, H, and N Takei. « Recent Progress in Animal Modeling of Immune Inflammatory Processes in Schizophrenia: Implication of Specific Cytokines. » Neuroscience Research 56.1 (2006): 2-13.
12. Boksa, Patricia. « Of Rats and Schizophrenia. » Journal of Psychiatry Neuroscience 32.1 (2007): 8-10.