I was excited to see that this week’s papers are on schizophrenia. It’s such an interesting disease with such complicated pathology. I started with the Kellendonk paper, and thought it was really cool that they tried to address the negative, cognitive symptoms of schizophrenia that are often ignored. It was great to see that they were able to find a model for these symptoms by overexpressing the D2 receptors in the striatum, and it was really interesting that the overexpression only needs to occur prenatally – this for me puts so much weight to the developmental roots of the disease. I thought this paper had a really good discussion, because they went into detail in how the overexpression of D2 receptors could cause the phenotype of cognitive impairments. It’s really interesting that it might not be the striatum itself, but rather the downstream effects of D2R overexpression on the D1 receptors in the PFC that leads to the working memory deficits seen in the model. It’s pretty crazy how complicated development is, and pretty amazing that things don’t go wrong more often. Kellendonk et al also talk about normalizing the D2R overexpression in adult mice, and that doing this actually results in a more severe phenotype. This really surprised me, and made me think about how this could relate to patients that are given anti-psychotics that are D2 receptor antagonists. Could this medication somehow be ameliorating their positive symptoms, but worsening the negative symptoms? I haven’t read up on how schizophrenic patients feel after taking that medication, but maybe some of the side effects have to do with this result that Kellendonk observed. One thing I wasn’t clear on in this paper were the NMDA lesion experiments. I didn’t really understand what they were trying to do there… What also confused me was one statement “control mice in this experiment performed better than control mice in other DNMTS T-maze experiments, most likely because of differences in housing conditions” – what were the differences in housing conditions, and if this is the case why did the authors use this data? Other than this instance though, I did not find any data remarks that made me doubt this paper.
The Moore et al paper was also very interesting. I have heard of the MAM model during my research, so my first question was whether this was the first paper introducing this model of schizophrenia. Later on I realized that Moore had referenced a paper of his from 1998 and 2001 regarding the MAM model. I was pretty impressed that this model was fairly old. I would be interested to learn more about how they came up with the idea of using a methylating agent as a way to create schizophrenic symptoms. If they did start work on this model in 1998, it took them 8 years to definitively prove its use as a model for schizophrenia. What impressed me most about this model was that it had developmental changes that occurred during or after puberty, just like schizophrenia presents in humans. I feel like that is one of the most interesting parts about the disease, and probably has really complicated pathology. The part I didn’t understand in this paper was the experiments regarding giving the rats amphetamine. What does giving them amphetamine have to do with the initiation of psychosis? Is there something that happens in humans during the first episode of psychosis that is similar to a dose of amphetamine? And I would be interested to know why they chose PCP as their amphetamine. I don’t know too much about these drugs, but I do know that PCP is a really strong drug that itself induces a type of grandiose psychosis, so I wonder whether those effects of the drug are important to the experiment. Otherwise, I thought this paper did a great job of going step by step through the reasoning of why this E17 MAM model is a good model for schizophrenia, and it was great to learn about the research behind this model that I have heard so much about.