Modeling Schizophrenia in Rodents - Emily Jones

Published in the same year, our two papers this week focused on two different models of schizophrenia in mice. Kellendonk et al. (2006) used a pharmacological lens, in their exploration of the DA hypothesis, which posits that an excess number of dopamine receptors, or over-sensitive receptors contributes to the pathology of schizophrenia. On the other hand, Moore et al. (2006) argues for a more developmental model using MAM, critically at the 17th day of embryonic development. 
It was acknowledged in Kellendonk et al. that drugs commonly used to treat schizophrenia are antipsychotics that block D2 receptors. However, these drugs only seem to improve positive symptoms. So to determine whether or not there is a causal relationship between D2 receptors and negative symptoms (cognitive deficits), researchers used transgenic mice that overexpressed D2R in the striatum. But if there is a significant relationship then why don’t we see significant effects in patients with schizophrenia being treated with antipsychotics that block D2R? Kellendonk and colleagues also implicated D2 receptors in a downstream effect, activating D1 receptors, which then mediate cognitive deficits. If D1R turn out to be the true culprit behind negative symptoms of schizophrenia, perhaps our drug treatments of the illness could change focus to block D1R instead of D2R. Researchers also explained that it may be too late for these drugs because typically at the time of treatment, physiological changes responsible for cognitive deficits have already taken place.
Moore et al. took advantage of a critical stage in rat embryonic development. MAM was injected in experimental dams at the 17th day of pregnancy, disrupting cerebral cortical development. Although researchers in this study did have reasonable control groups, I still can’t help but feel that temporal precision was low. The paper studies the affected offsprings after they had matured (at 4-8 months of age), leaving for a period of developmental time unaccounted for. In addition, unlike Kellendonk et al., there was not a way to reverse the effects of MAM on development so the only comparison groups are E15 and no MAM control. 
Overall, the two papers take us through models of various aspects of schizophrenia. Neither claim be perfect replicas of the illness in rodents, but avenues through which different symptoms and prognoses of schizophrenia can be picked apart and studied. 

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