Week 6: Kellendonk and Moore

This week's papers addressed the mental illness of schizophrenia. Although schizophrenia is very complicated and not fully-understood, Moore et al and Kellendonk et al both presented rather convincing arguments for why their models directly applied to schizophrenia. Personally, I preferred Kellendonk's paper, as I found it to be more concise and direct. I appreciated that Kellendonk et al acknowledged the difficulty in modeling such a disease and chose to focus on only one component. By doing so, they were able to delve deep into the topic of D2 receptors in the striatum and present very strong evidence to support their hypothesis that increased activity of D2Rs in the developing striatum can cause the behavioral and working memory deficits that are present in schizophrenia. They also demonstrated that this increases dopamine levels, decreases dopamine turnover, and increases D1Rs in the mPFC, which may explain the behavioral phenotype. Throughout the paper, Kellendonk et al acknowledged any potential weaknesses and gave multiple hypotheses and reasoning behind each, as well as directions for future research. I believe this paper provided a strong foundation to build upon, and I'm interested to see the follow-up research done by the team in the past 9 years since this was published.

I found Moore et al's paper slightly more difficult to follow, but they still provided strong evidence for their model of schizophrenia. MAM-E15 mice were a wise comparison to the MAM-E17 mice as they helped Moore et al resolve the previous controversy about using MAM as a model of schizophrenia. Moore et al were able to show that while E15 is too early and will not produce the schizophrenic symptoms (instead producing microencephaly and gross motor impairments), E17 is a more ideal time for MAM exposure to create a schizophrenic model. Exposure at E17 led to the behavioral, cognitive, and neuroanatomical deficits that are characteristic of schizophrenia, presenting a strong case for this model. However, Moore et al also recognized the complexity of schizophrenia, and until we know much more about the intricacies of the disease, we will not have an ideal animal model. Both papers presented different but convincing proposals, which leads me to think they are both getting at important aspects of schizophrenia. 

Although the two papers took different approaches towards schizophrenia, there was quite a bit of overlap and similarities. The most interesting part to me was the fact that manipulations to the animal models were done during development in order to get the model of schizophrenia. Kellendonk et al performed a clear experiment in which they gave doxycycline to adults, which turned off the genes responsible for increasing D2Rs. They failed to see an improvement in working memory, indicating that developmental/chronic increase in D2Rs is sufficient to cause the schizophrenia-like phenotype in adults.

Moore et al also discussed this topic, as they exposed their animals to MAM during development as well. One figure I found especially interesting was Figure 10, as it showed the differences in response to amphetamine in prepubertal and adult mice. In humans, schizophrenia generally doesn't present any symptoms until early adulthood (around age 20), so I found it especially convincing that these mice experienced a similar delayed onset of symptoms. Since I read the Kellendonk paper first, I had actually been wondering whether this topic would be addressed and I'm excited to see that Moore et al was able to produce a model with this late onset.

In terms of finding a treatment or prevention method, it seems unlikely simply due to the fact that development is pointed out as the crucial time period. Moore et al briefly discussed possible identification of early behavioral and physiological biomarkers to develop preventative treatments, but I still don't quite understand how we could treat/prevent schizophrenia if it must be addressed during early development. I'm sure much more research has been done since 2006 though, and I recognize that these articles only have a very small piece of the whole story.