Models of Schizophrenia


Moore et al. focused on the existing hypothesis that schizophrenia is a result of abnormal brain development, particularly in frontal and limbic cortical circuits and dopaminergic inputs to the striatum. The current study used MAM to disrupt development of E15 and E17 mice, focusing on the effect on the morphology of paralimbic frontal/temporal cortices and medial dorsal/midline thalamic nuclei. Furthermore, corticostriatal circuit function was analyzed to extend research on cognitive deficits in MAM-E17 mice. MAM decreased brain weight and universal brain region size in both E15 and E17 groups, even though the MAM-E17 group showed no change in number of cells. MAM-E17 showed a more schizophrenic-like decrease in grey matter and an increase in density in the prefrontal/cingulate and insular/perirhinal zones. These neurons in the prefrontal cortex showed a more depolarized resting potential and spike threshold, and the average spike threshold was more depolarized. Behavioral abnormalities included a deficit in prepulse inhibition, increased orofacial dyskinesias and stereotypes, and a deficit in reversal learning (not novel discrimination) in MAM-E17 mice. Overall, the data weigh in on previous studies, showing that MAM-E17 exposure affects numerous behavioral and neuroanatomical measures.
Kellendonk et al. studied a different dysfunction in the schizophrenic brain: D2 receptors. They created mice expressing increased D2 receptors in the striatum. This expression was capable of being temporally and spatially controlled. These mice showed no difference in hyperlocomotor activity, sensory gating, or anxiety. Overall, overexpressing D2 receptors affected working memory and behavioral flexibility tasks, as measured by two delayed non-match to sample maze tasks and an olfaction discrimination task. Animals were then fed doxycycline to stop gene expression. These deficits remained, indicating the cognitive deficits aren’t easily reversed and may be developmental or chronic. The authors hypothesized that the excess D2 receptors affect the efficiency of the cortico-striatal synapses, therefore contributing to cognitive impairment.
These two papers showed different approaches to studying specific schizophrenia-related dysfunctions. I found both interesting, as I have heard about the underlying theories on D2 receptors and the prefrontal cortex. I’m interested in learning more about what is being done to create models for diagnosing and treating schizophrenia, especially since schizophrenia is one of the more elusive disorders. Science is always changing, and the models used to represent it will have to change too. It doesn’t help that it’s impossible to create a true mouse model of schizophrenia. As the articles mentioned, some cognitive symptoms cannot be measured. As a result, research must settle for modeling the different components. I also wonder how these different components interact with one another in the human mind, creating a cohesive diagnosis of schizophrenia, and how this overlap can be accounted for in animal models.

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