Neonatal low-dose domoic acid exposure during a critical period of central nervous system development: A potential animal model of schizophrenia

Schizophrenia is a complex and devastating mental disorder, found to affect up to 1% of the general population. Characterized by a variety of positive, negative and cognitive symptoms, this debilitating disease results in great emotional cost to people affected, as well as in significant financial cost to the economy. While the etiology of schizophrenia is not yet known, it is believed that factors which occur during development, long before the formal onset of the disorder, may result in permanent alterations to the central nervous system. Animal models provide one of the best ways to study many complex human disorders, like schizophrenia. While a number of animal model of schizophrenia exist, no model is ideal and much about the disorder still remains to be understood. New models, as well as improvements on current models have the potential to add significantly to our understanding of schizophrenia and will undoubtedly benefit the human clinical practice.

Past research has indicated that neonatal administration of low doses (20μg/kg) of domoic acid (DOM) (a glutamate agonist) to rats during a critical period of central nervous system development (postnatal days 8-14), shows potential as an animal model of schizophrenia. The purpose of this thesis was to further investigate this potential. This was achieved using two behavioural tests considered to be the "gold standards" for an animal model of the disorder, prepulse inhibition (PPI) and latent inhibition (LI, as well as assessing brain tissue for changes in GAD67 in the hippocampus, a common alteration found in the clinical population.

Results indicate that neonatal DOM treatment results in significantly lowered PPI compared to controls, but that this effect can vary depending on the sex of the animal, the time of day during which testing occurs, and the prepulse level used. Neonatal DOM treatment also resulted in a significant decrease in LI, with the effect seen in males 24 hours after conditioning and in females 7-8 days after conditioning. The analysis of GAD67 in the hippocampus revealed that DOM-treated females displayed significantly less GAD67 in the left CA3. While this effect was not seen in the right hemisphere or in the male animals, subsequent qualitative analysis indicated that small alterations to the immunohistochemical procedure (such as a decrease in background staining) may improve the quality of the analysis. In conclusion, neonatal low-dose DOM treatment has succeeded in demonstrating both face and construct validity for an animal model of schizophrenia. Additionally, the method through which the model is created, is consistent with at least some of the current etiological understanding of how the disorder is produced. While further study is required to better understand these changes and predictive validity has yet to be investigated, these results indicate that neonatal low-dose treatment of DOM shows great promise as an animal model of schizophrenia.