Assessment of the face validity, construct validity, and etiological validity of a novel animal model of schizophrenia

Abstract

Schizophrenia is a devastating neurological disorder that affects approximately 1% of the population and is characterized by positive, negative, and/or cognitive symptoms. Positive symptoms are associated with increased glutamate (Glu) and/or dopamine (DA) signaling in the nucleus accumbens (NAcc) while negative and cognitive symptoms are related to decreased Glu and/or DA signaling in the medial prefrontal cortex (mPFC) and hippocampus. The etiology of the disorder remains unknown, yet it is believed to be the result of a combination of genetic and neurodevelopmental factors. In order to improve our understanding of schizophrenia it is important to develop and further characterize animal models with relevance to the human condition. Prior research has demonstrated that rodents exposed to neonatal treatment with domoic acid (DOM) (20 ìg/kg), a kainate (KA) receptor (KAR) agonist, during a critical period of brain development (i.e. post-natal day (PND) 8-14) produces animals that exhibit several behavioural, neurochemical, and neuroanatomical abnormalities that are characteristic of schizophrenia. The purpose of this thesis is to further examine the potential of DOM treatment in producing an animal model of schizophrenia by assessing cognitive functioning (i.e. face validity) using the attentional set-shifting and puzzle box paradigms, employing immunohistochemistry to examine dopamine transporter (DAT), D1 receptor, and D2 receptor as markers of the DA system in the mPFC (i.e. construct validity), and by assessing active caspase-3, an executioner caspase in cellular apoptosis, in the mPFC (i.e. etiological validity). Behavioural results indicate improved cognitive flexibility among DOM-treated males in the attentional set-shifting paradigm and improved short-term memory and problem solving ability among DOM-treated females in the puzzle box. Neurochemical results indicate increased DAT staining in the right PRL of DOM-treated females, decreased caspase-3 staining, as evidenced by optical density measurement, in the right PRL among DOM-treated males, and decreased caspase-3 staining, as evidenced by cell count measurement, in the right PRL among DOM-treated females. These results serve to strengthen the face validity, construct validity, and etiological validity of the model as they demonstrate cognitive alterations, neurochemical alterations in adulthood which are associated with behavioural symptomatology, and neurochemical alterations during development