Week 6

I found the Kellendonk et al. paper to be pretty straightforward. Their formatting, specifically the headlines before each section made it very easy to follow. I also found it very specific. They start off talking about schizophrenia and how we need to understand the underlying mechanisms and then zoom all the way in to D2 receptors and how it affects D1 receptors in the PFC. I just felt like their scope or reasoning dwindled as the paper went on in that their experiments don’t really seem to tie back to their proposed larger picture. It just feels like they are sort of throwing this fact out into the world and saying “not really sure what this means but its important.” Outside of that, I thought their experiments and findings were valid.

The Moore et al. paper was interesting in terms of being very different from papers we have previously read. It was easier to read as they pretty much just documented their fancy model which, to me, was a nice break from super confusing papers with crazy figures we have recently read. It was a nice pairing with the Kellendonk paper in terms of their focus on schizophrenia but I liked how there was a firmer conclusion in the Moore paper, in terms of the experiments relating back to schizophrenia. That made the difference for me in my preference of Moore over Kellendonk.

Week 6

The first paper I read was Kellendonk et al.'s, which I found very interesting and thorough. While I've never studied schizophrenia, I found this paper giving enough in-depth background to understand their studies. While reading, I felt that the paper was so thorough that it actually became a bit repetitive. By the end, there was an accumulation of support for D2 activation and its major role in the striatum. In addition, this was connected with an increase in D1 activation in the prefrontal cortex, which led to a decrease in working memory functioning. However, and this may be due to my lack of neuroanatomy and understanding of circuits, I'm unclear on how the alteration in D1 activity led to the behavioral symptoms of cognitive deficits. In addition, it would be interesting to see how D1 antagonists could be used clinically to alleviate cognitive behaviors associated with schizophrenia and not yet addressed by current medication (I did notice they mentioned D1 antagonists in the discussion, but were inconclusive in their ultimate effectiveness). I think one of the most interesting clinical points that the authors brought up was that if turning off the D2 receptor enhancement did not affect the cognitive deficits, how could we treat schizophrenic patients if their brains have already adapted in line with this schizophrenic model? This idea is pretty grim for schizophrenic treatment, and I think more research should be done into how these alterations come about and what can be done to prevent permanent morphologies. 

Moore et al.'s paper was, in my opinion, the outlier of all of the papers we read. As I often criticize the realities of animal models, I believe this paper was extremely useful in providing the outline to how to create a proper animal model and thorough ways in which to test it. This paper, while starkingly different, provided an appropriate compliment to Kellendonk et al.'s, who claimed that genetic manipulation, while useful, is extremely limited in scope. Additionally, if the E17 is actually representative of a clinical model, this could be instrumental in providing biomarkers in order to prevent morphological changes before it's "too late". I think the E17 model proves, at least by my standards, representative of schizophrenia, and because of its focus on development from the root cause, it seems to be more reliable and informative. 

Kellendonk & Moore

The question in the Kellendonk paper asks what the behavioral and physiological consequences of increased D2 receptor function is in the rodent striatum. However, based on previous research, we already basically know what will happen when we increase D2R function in the rodent striatum – what we really want to know from this paper is how doing this will fit into the various hypotheses regarding the origin of DA dysfunction and its consequences in the schizophrenic brain.

While most of the paper was spent proving that the outcome of the manipulations on D2 transgenic mice worked/was what they expected it to be, the important findings (in my opinion) were that the cognitive deficits were not reversible along with D2 receptor hyperfunction in the striatum, plus the incurrence of compensation in mPFC D1 receptor function. Results suggest bidirectionality in the system and offer two possible explanations for the homeostatic mechanism apparent between D2 receptors in the subcortex and cortical D1.

This paper is awesome for paving the way for future study, but I do disagree with the last line; I don’t think that we can extrapolate from these results that this study has achieved confirmation of causality (ie, that D2 receptor gene polymorphism causes D2R dysfunction which causes D1R compensation).

The Moore paper is more extensive as a model of schizophrenia than the Kellendonk paper, but each has problems – in this model, all pathology “boxes” are checked, but the mechanism of MAM methylation on E17 is not explored. Testing what developmental processes occur on that day shouldn’t be hard in a rodent model. But that seems to me the right next step for this research.

This model tackles the DA problem at an interesting angle (hyperresponse to psychoactive drugs) but is naïve to the subtleties of the DA receptor balance that the Kellendonk paper examined. The Moore model doesn’t rule out the validity of the Kellendonk model, especially when considering the possibility that a DAR polymorphism is responsible for DAR dysfunction – perhaps this is a development on E17?

Week 6

Both papers explore the pathology of schizophrenia, with Kellendonk exploring the cause of D2 abnormalities often seen in the PFC of effected patients, and Moore uses a systems analysis to demonstrate a rat model of schizophrenia. I felt the Moore article was pretty expansive in its evidence that E17 was an effective model. I liked how the E17 rats were studied through a series of different tests from prepulse inhibition startle, oralfacial dyskensia testing, reversal learning tasks and locomotor response tasks at different ages. I find their inclusion of all these different symptoms of schizophrenia into the animal model makes it much more convincing, especially alongside of the controls. I'm interested in the historical significance of these paper as I know neuroscientists have been making great strides in both understanding schizophrenia as well as treating it and I am curious how this paper, as well as Kellendonk's have played roles in this expanding knowledge.

Kellendonk notably does not see any unaltered locomotor activity, sensorimotor gating, and generalized anxiety in his models of mice overexpressing D2 receptors. I am curious if this means a failure of Kellendonks model or evidence that D2 overexpression is more relevant to the pathology of schizophrenia effecting cognitive functioning. Moore's model does see this change in behavior as well as cognition. I also am curious what changes between mouse and rat models, specifically to schizophrenia and affected brain regions, and how do we need to think about them differently?

Week VI

This set of papers read differently compared to the other papers covered in class so far. In the past the papers we have read have focused on investigating a new aspect of anxiety or depression based on pre-established models. This week however, the focus of Moore et al. was the creation of a rodent model of schizophrenia, while Kellendock et al. focused on D2 receptor overexpression.

            After reading Kellendock et al. my first impression was “The researchers still don’t know anything definitive about the etiology of the cognitive symptoms. They just know a polymorphism in the D2 receptor gene increased D2 ligand binding.” I was definitely convinced that the dopamine system is implicated in the pathology of schizophrenia, but I still was not sure how; I had trouble seeing the big picture. The authors mentioned in their introduction that “the genetics of most mental illness is polygenic and complex” as opposed to the genetics of neurological illness.” Consequently, the researchers decided to focus on a very specific aspect of the disease, in this case the link between dysfunction of dopamine D2 transmission and deficits in working memory and behavioral flexibility. In my Clinical Neuroscience class I noticed a trend, whenever we studied a different disease we would learn that there was some abnormality in the patient’s brain, but we would never learn in which direction the implications of said abnormality leaned. All the researchers knew was something was different, but did not know specifically how said differences affected the patient. I found that trend to be present when reading this paper. The researchers had all of these findings such as D2 mice having altered glucose metabolism, or D2Rs in the striatum affected D1R activation in the mPFC, but said finding seemed isolating and did not integrate well into the overall narrative of the paper.

To be fair, I also feel that had I had a stronger background in schizophrenia research this paper may have read more smoothly. If that had been the base I may have been able to see connections between the etiology of the disease and the corresponding finding in the paper. The same can be said for the Moore paper. Based on my limited knowledge of schizophrenia it seemed like the researchers had created a successful rodent model, but without further background knowledge it is difficult to be critical.

Week 6

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.

Week 6: Kellendonk and Moore

Both of these articles adequately demonstrate a pathological basis for schizophrenia. The Kellendonk article and the Moore article use cross-checking methods to make sure that the results they are seeing aren’t due to any additional factors. This is especially important for the Moore article because an important piece was proving that MAM utilization at E17 was more accurate in demonstrating schizophrenia than those previously administered on E15. I think that each article does a great job in experimentally showing how these pathologies influence schizophrenia-like behavior, but one thing I found interesting is that in some of the behavioral observations, these papers actually differed. For example, Moore states that there was a significant deficit in prepulse inhibition, whereas Kellendonk found “no differences in the attenuation of the response to the acoustic stimulus after the prepulse.” Moore also found that there was a significant deficit in reversal learning, where Kellendonk found “a mild deficit in reversal to the rule.” These two somewhat contrasting results make more sense when remembering that mental illnesses are extremely complex diseases with often multiple pathologies. It is extremely possible that poor development influenced by MAM could cause deficits in prepulse inhibition and reversal learning, while an increase in D2 receptors may not cause that behavioral phenotype. Both of these schizophrenic pathologies may be working together to create the complete behavioral picture of the disease. While these papers are trying to stand alone as an explanation to schizophrenia, they need to take into account other pathological findings that may occur at the same time in patients that suffer from this illness.

Another interesting finding by Kellendonk was that D2 receptors are expressed in the striatum at E17.5, which would occur after Moore administered the MAM to her E17 pups. This could also account for the differences seen between these two studies. The use of MAM did not allow for the development of D2 receptors necessary for a schizophrenic phenotype, and thus, Moore obtained results that differ than those influenced by D2 receptors.