Week 6

Both of this week’s papers addressed the pathology of schizophrenia. I have never read papers about schizophrenia before, so these papers were particularly interesting, especially because schizophrenia is such a fascinating and complicated disease. The two papers tackled different aspects of schizophrenia's complex pathology; Moore et. al administered a methylating agent to embryonic mice and discussed resulting cerebral cortical development and schizophrenic-like symptoms, while Kellendonk et. al focused on the dysregulation of D2 receptors implicated in this pathogenesis. I first read Moore et. al’s paper and found this to be a convincing presentation of the MAM model in creating schizophrenic symptoms. I also enjoyed reading about the various behavioral tests (orofacial dyskinesia, reversal learning, locomotor responses, etc.) that are used to verify cognitive and motor deficits seen in schizophrenia; the inclusion of these various tests absolutely strengthens their findings. For the most part, I found the Moore paper to be comprehensible despite my lack of background knowledge regarding schizophrenia animal models; however, I was confused about the prepulse inhibition test and exactly how this test is conducted. I also had questions regarding the use of amphetamine as a test for locomotor response and how the use of this drug is relevant as a behavioral test for schizophrenia.

Regarding the Kellendonk et. al paper, I was most confused about the finding regarding the D1 receptors’ involvement in overactive D2 receptor activation and subsequent working memory deficits. I found this paper easy to follow until Figure 6 when D1 receptors were introduced; this may be due to a lack of understanding regarding the circuits involved and the specific receptor properties of D1 and D2. Regardless, I found it to be difficult to make sense this finding, and I'm hoping we elaborate on this particular figure in class.

Finally, I did notice both of these papers were published in 2006; it would be interesting to see how dramatically subsequent research has elaborated on these findings since these publications.

Week 6

Kellendonk et al make measured statements throughout the paper as to not suggest that they are overinterpreting their data and the implications. Both the title and the introduction make it clear that, though the findings show similarities with schizophrenia and it is possible that D2 receptors are involved in the cognitive impairments characteristic of the disease, the most they can say conclusively is that the overexpression of D2 causes cognitive impairment phenotypes in their transgenic animals. The experiments themselves are simple and straightforward but I found the experiment in Figure 6F difficult to interpret. I am not sure what to make of this experiment, in which adult animals that were fed doxycycline for 14 days showed a significant decrease in the number of c-fos positive neurons. Here’s a little bit of background to explain my confusion:

First, they state that the D2 overexpression decreased DA turnover and therefore increased DA levels in the previous section. Then, they state that depletion of DA increases D1 ligand binding in rat models, which makes me think that D2 overexpression should cause decrease D1 activation/ligand binding. Next, they show that animals with D2 overexpression increases c-fos expression with the addition of D1/5 agonist, suggesting that D2 overexpression is actually causing more D1 activation, which is the opposite of what I expected based on the previous information. Finally, they show the experiment in Figure 6F, which then suggests that maybe something more complicated than D2 dependent alteration in D1 ligand binding is at work. I know they say that the results in Figure 6F suggest, “that [the animals] developed compensatory processes for D1 receptor function that are independent of concurrent D2 receptor function,” but I cannot for the life of me understand what the implications of this are in combination with the  previous experiment and how this fits in with the rest of their hypothesized/potential model for cognitive impairment in schizophrenia.

The MAM experiment in the Moore et al paper seems incredibly heavy handed, but as Kellendock et al point out in the first paper, they are limited by the little knowledge they have on the biological basis of mental illness so you have to start somewhere. That said, administering MAM on E17 to prevent inducing microcephaly was well reasoned in the introduction, but the treatment still causes widespread changes, and likely dysfunction, throughout most of the cortex. I would be surprised if they didn’t find evidence to suggest phenotypes characteristic of most mental illnesses are likely to result from this, not just schizophrenia, at which point the conclusions of this experiments lose some impact. I’m less interested in what was wrong with the animals, because it seems like it would be and is a lot, and more interested in what cortical functions managed to remain intact. The decreased number of trials required for MAM-E17 animals to learn the novel discrimination task would be an example.

The part of the paper that struck me was the last line, which states: “Finally, perhaps the most innovative use of such a model may be to identify early behavioral physiological abnormalities that may serve as biomarkers for preventative treatments.” I agree with the preceding statement which states that these model can be used to identify genes that regulate development of cortical circuits, in fact I think this is its best use as a developmental model, but the final line seemed far-fetched. The proposal seemed like a catch-22 because, if this is a good simulation of the start of the disease, then their experiments suggest you are doomed from the get-go and there is no preventative measure you can take. Or, if this is a sufficient way to induce the symptoms of the illness even if it is not the natural progression of the disease, then any kind of early identifiers in this model are not liable to be indicative of the ones we would see in the progression of the actual disease. Not to mention there is a high likelihood that these animals probably don’t go through a “progression” of any sort and instead are phenotypically altered from birth, which is distinct from schizophrenic individuals who don’t show cognitive symptoms until late adolescence.

week 7

I thoroughly enjoyed reading these weeks articles and found them refreshing to read because they presented a new disease, schizophrenia, to study and different methods in which to study the disease. I preferred the Ayhan et. Al paper studying the neurodevelopmental origin of schizophrenia. When did the effects of the gene, Disrupted-In Schizophrenia-1 (DISC1), mutating develop abnormalities in the brain to become schizophrenia or other mood disorders. Through my first read through this article, it was a bit difficult understanding how exactly their method of expressing mutant hDISC1 in mice was done. Maybe I got lost in all the details, but if the presenters could possibly review how this was done I would have a better understanding, specifically going over Figure 1A. What I found the most interesting about the Ayhan et. Al paper was that they used both male and female mice to conduct the study and they were able to extract data that was more prominent in one sex compared to another. Female mice go through their 4-day Estrous cycle so I wonder if that had an effect in female mice showing increased depressive like symptoms. Thinking about this in its clinical application to humans, knowing that the effects of mutant DISC1 depends on when the protein is expressed, would we be able to do DNA tests before let’s say a baby is born to be able to prevent the protein from being expressed. I feel as though I am approaching “Designer Baby” space of genetics, but if we know what gene largely expresses schizophrenic phenotypes would we be able to prevent that expression in any way. As for the Burrows et al paper, I really found it interesting that they were studying the effects of environment in the expression of the schizophrenic phenotype. This paper countered argued the first paper by saying it does not only come down to nature (genetics) but also nurture (environment). My only quarrel with the paper was that it did not seem to include both sexes of mice since they did not find a significance difference. Furthermore taking this paper into use clinically for humans, would an early intervention in providing a healthy, stimulating environment for those pre-disposed to express the mutant DISC1 gene help prevent that expression or rather delay it? 

Week 6

Schizophrenia has always been one of my interests in the field of neuroscience so I was very excited to finally begin this set of papers. I also just read Brain on Fire which details a NMDA-autoimmune disease that results is oftentimes misdiagnosed as schizophrenia due to symptom similarity. I really enjoyed reading more about the role of NMDA receptors in relation to these symptoms after finishing Brain on Fire.

While there are definitely certain symptoms of schizophrenia that are able to be observed (catatonia, aggression, repetitive movements, etc.), there are others that are difficult to visualize (hallucinations, paranoia, etc.). This has always caused me to wonder if scientists will ever be able to develop a strong animal model for schizophrenia. Upon reading the Kellendonk et al. paper my feelings still hadn't changed; though I do believe that the dopaminergic system does have implications in schizophrenic symptoms. That said, I also believe that given the wide range and variety of symptoms present with schizophrenia a multitude of neurotransmitter systems are most likely also involved. Another component of the paper that I couldn't totally grasp was the back and forth comparison with rats. I understand that there are certain studies done with rats that have led to information that can relate to aspects of this paper, but I would have assumed that there were other studies done in mice that could have been used instead to keep the comparison within species. I had to reread a few sections to clearly differentiate discussions regarding previous papers utilizing rats from discussions of the current study's data on the transgenic mice used. I did, however, find it interesting that the impairment in the working memory task was not corrected with the application of dox to turn off the transgene and the excess D2 receptor expression.

Briefly on the Moore et al. paper: I enjoyed the thorough process of detailing the creation of an animal model, especially of schizophrenia. Obviously there are improvements to be made within the model, as is the same with most, but I found it a helpful discussion. My reservations still remain however, given that symptoms such as hallucinations and paranoia, which are very characteristic of schizophrenia, are not able to be observed in this animal model.

Week 6

This week’s topic is super exciting as I have always been interested in learning more about schizophrenia and the neural implications underlying the disorder. I thought Kellendonk’s paper was well drafted and the experiments were easy to understand and follow, but I wasn’t fully convinced with their results and how they were related to the hypothesis. I found it unusual that mice overexpressing D2 receptors in the striatum showed unaltered locomotor activity, sensorimotor gating and GAD, considering how impaired D2 activity is one of the primary factors in the diagnosis of the disorder. It made me wonder if this could possibly reflect an overestimation of its role? I was also confused about whether overexpression of these receptors at birth or developmentally is responsible for the deficits, because the result that normalizing D2 expression in adult mice could result in a more severe phenotype is quite bizarre. Lucia pointed out clinical implications of this result and I agree with her, what does it mean for patients consuming drugs to normalize their D2 levels? Does it only help them for certain symptoms and worsen the others? I also found it super cool that it might not be the overexpression of D2 alone but rather its downstream effects on D1 and its interaction with the PFC that together might be causing the working memory deficits. I wish they had expanded more on this because it would be interesting to know how that interaction works. It truly highlights how complicated this disorder is and how there’s so much more to investigate and learn about. Moore et al. did a good job at explaining in a very detailed manner as to why MAM-E17 is a better model for schizophrenia compared to past models. I’ve heard about this model in the past and know that it is commonly used so it was noteworthy to learn about why specifically this particular model exhibits symptoms more similar to those seen with the disorder.

Week 6

This week, both papers, released in the same year, focused around producing rodent models of schizophrenia. Both recognized a developmental dysregulation inherent in the formation of the disease, albeit via different mechanisms. Kellendonk et al. found overexpression of D2 receptors in the transgenic mouse striatum to be sufficient to induce schizophrenic symptomology such as deficits to working memory, and physically induce changes to D1 transmission in the prefrontal cortex which may be related to the cognitive effects seen in the model. However, Moore et al. studied disruption of embryonic brain development in mice using methylazoxymethanol acetate (MAM) and its usage in producing a schizophrenic model. In their study, Moore et al. found that MAM resulted in general microencephaly and greater deficits to motion, executive control, and prepulse inhibition, and while there were selective decreases in cortical thickness in later exposure of MAM, early of exposure led to general microencephaly.

            Ultimately, this week’s discussion revolves around the question of a preference between two models of schizophrenia and whether one study provides a more thorough argument. At first, Kellendonk appeared to be a more convincing paper as it directly studied dopamine which has been classically associated with schizophrenia. As well, alterations to D2R specifically in the striatum would theoretically have an effect on the output of the corticostriatal pathway which may be reflected in the alterations in D1 activity in the PFC which may be cause of typical schizophrenia symptoms. Another interesting aspect uncovered in this study was the irreversibility of effects of developmental overexpression of D2R, if not greater severity induced by such an attempt at regulation. While I was initially skeptical of Moore et al.’s findings as it seemed more blunt in its focus on premature pharmacological cessation of cortical development without focus on neurotransmitter activity, their correlates between former findings in schizophrenia and findings in their own study were convincing at least from a neurological standpoint, and their use of orbitofacial activity measures was if nothing else novel and interesting. Ideally these two models could be combined, possibly with a more specific focus on cell identity in the Moore-style model.

Week 6

Starting with the Kellendonk et al article, I felt as if it was a nice change from what we have been reading recently. Though there were times it was a bit wordy, the experiment was easy to follow and the results were convincing. I thought it was interesting how they used what they knew to be true in rats brains and applied it to the mice, using lesions to see if the brain areas and functions of mice were homologous to the already well-researched rats.  I would be interested if they delved more into the idea that the developmental expression of D2 receptors is what causes the cognitive effects, not just the concurrent expression. What occurs during development that allows the D2 receptor expression to cause cognitive deficits? By what mechanism is this happening? Another point I found interesting was that too much or too little D1 activation leads to deficits in working memory. This shows what a complex disorder schizophrenia is and why it is so difficult to treat. I'd be curious to learn more about the optimal D1 activation in working memory and what effects too much or too little activation would have.
Moore et al was different from most of the papers we read so far, and though I found it hard to fully comprehend the details, I found the end result convincing. I've never read about the process of finding a model animal for a specific disease so I found this eye-opening. Only one point of contention I had was that I did not quite understand why the E15 rats were sporadically included throughout. I did, however, appreciate how thorough the testing was for determining the E17 to be a good model. I did not even think of how great the implications were for this until reading the final paragraph. With this more accurate model, its possible to not only test potential drugs, but actually observe the pathophysiology of the disease as it begins and progresses, something we cannot do in humans until symptoms have shown and a diagnoses has been made.