Burrows et al.

Burrows et al.

            While reading Burrows et al., it was interesting to see the gene-environment interactions when knocking out mGlu5 and introducing environmental enrichment. The authors postulate “EE has been shown to upregulate NMDAR subunits” and this is demonstrated by the fact that EE seems to ameliorate schizophrenia related symptoms when the mGlu5 gene, another glutamate receptor is knocked out. mGlu5 tends to regulate the toxicity of glutamate and too much glutamate could be the cause for many of these schizophrenia like symptoms.

            It is interesting to see though that when NMDA antagonists such as MK-801 are introduced, EE seems to actually worsen symptoms of schizophrenia. For example, in the photo-beam arena, following the light being turned on, the KO mice in the environmental enrichment condition actually exhibited more locomotive activity, characteristic of schizophrenia. Similarly, in the pre pulse inhibition test, KO mice in the experimental condition were not able to inhibit their startle response as mice in other conditions. Both of these tasks involved the administration of MK-801 indicating NMDA receptor function can be impaired by the manipulation.

            Overall, I think Burrows et al. do a good job using supporting evidence for their model of environmental enrichment ameliorating schizophrenia-related symptoms in mGlu5 knockout mice. They demonstrate that glutamate toxicity has potential for schizophrenia etiology, i.e. support for the glutamate hypothesis. However, there are many variables involved. Environmental enrichment upregulates NMDA receptor subunits to prevent toxicity but also the function of knocking out a glutamate receptor impairs NMDA function implying that the system somehow works in concert.

Kellondock et al

Kellondock et al

I found the Kellondock et al article to be interesting due to the fact that it approached schizophrenia with focus on the D2 receptor. One of the theories behind the cause of schizophrenic symptoms was the role of dopamine expression. Since schizophrenia encompasses a wide range of symptoms, it can be that dopamine activity may not be the only factor but it is a promising area of research. Kellondock et al was able to explain how the overexpression of D2 receptors led to working memory failure. Their findings showed that increasing the number of receptors does correlate to the lack of working memory.

However much like how schizophrenia can be caused by different factors, I don’t believe Kellondock et al succeeded in proving that D2 overexpression can conclusively determine whether or not schizophrenia is present. Just like how there are multiple symptoms of schizophrenia, they may not be caused by the same type of factor. If only working memory deficits are seen, it can be a good model to see if D2 plays a role in the disorder. Kellondock et al does a decent job of convincing the readers that there is a correlation between the D2 and memory deficits but it does not encompass why other symptoms of schizophrenia occur.

Much like Yiu et al tried to identify a model for post traumatic stress disorder, Kellondock et al does a decent job of identifying what may cause one particular symptom of schizophrenia. Schizophrenia is a complex disorder that can take on different types of symptoms and therefore can't be completely understood using one model. I believe Kellondock et al is onto a good path especially in the terms of dopamine roles but it is not completely convincing. The testing done demonstrated the slight correlation of dopamine but the results were not completely significant to prove the intentions of the model. I believe the paper had potential but it should try to address other symptoms as well.

Moore et al

With an “adolescent onset”, schizophrenia, without a doubt, is a neurodevelopmental disorder. Even though very rare, cases with 13 years old children have been evident. Moore et al does an impeccable job creating similar morphological differences in the brain that has been shown in patients with schizophrenia while using a rat model. 

By administering methylazoxymethanol acetate (MAM), a DNA-alkylating agent, on embryonic day 17 (E17), brought forth anatomical abnormalities in rats that are similar to schizophrenia.  MAM E17 rat model makes a great neurodevelopmental model for schizophrenia and has been viewed as the animal model of schizophrenia in the science community. Unlike previous research papers we have read, this paper looks at the Neuroanatomy rather than using behavioral testing. Being one of the major symptoms of patients with schizophrenia, hallucination would have been problematic to see in animals since there is no sufficient evidence regarding animals hallucinating. This comes from the fact that hallucinating related behaviors such as response to non-apparent stimuli, are viewed to be too non-specific for any research that is trying to look at the mechanisms of hallucinations. This makes looking at the dysfunction in genes, neurochemistry and Neuroanatomy in schizophrenia a more promising animal model.

Early administration of MAM in “Figure 4” showed less thickness and area in areas such as the PFC and hippocampus in MAM E15 than MAM 17. This shows the neurodevelopmental problem that causes these brain areas to decrease more in size when MAM is administered earlier. It would have been interesting to look at genetic predeterminants such as DISC-1, which is important when it comes to development. The DNA damage that was caused by MAM can help see which genes are involved in neurodevelopment and whether some of these genes might contribute to neurodegenration. Even though they mentioned how DNA methlyation may regulate the expression of certain genes, it would have been nice if they went along with it and put their ideas in action.

Also, in “Figure 7”, where they were measuring for ataxia, was not the best choice when it comes to looking at the neuropathology of schizophrenia. This is because MAM causes lack of muscle control and there is no association between ataxia and schizophrenia that I know of. There might have been a reason behind them choosing to go through with this particular experiment that I have overlooked. If this was a study on epilepsy, it could have been beneficial to measure the levels of ataxia.  

Moore and Kellendork

Both Moore and Kellendonk worked with animal models for schizophrenia, with Moore trying to create one and Kellendonk trying to improve one. I thought it interesting the success that Moore had using MAM to create mice with a schizophrenic phenotype. Kellendonk, on the other hand, did not have the overwhelming evidence of a successful model, as they were unable to cause a significant change in locomotion, gating, or anxiety in the mice. This may be due to the fact that Kellndonk targeted D2 receptors in the prefrontal cortex, whereas Moore used MAM to affect cortex development overall. Ultimately, Kellendonk didn’t affect the actual structure of the brains like Moore did, they only altered the dopamine neurons’ activity. I say dopamine neurons, because although they targeted the D2 receptors, the D1 receptors were also affected. It was also interesting that once they stopped expressing the gene that controlled the D2 receptors, the results were still being expressed. It would be interesting to study why this occurs, and how the activation of the D2 receptors specifically alters the brain to cause this.

Moore et al, a sum of parts.

Obviously when you take parts of a whole it is tough to see the big picture. If you take any of the individual behavioral tests out of Moore’s experimental protocol, they do not make me think of a model of schizophrenia. Most of the deficits noted in the results appear to be symptoms common across psychotic disorders. Modeling schizophrenia is a very complicated task. It is especially difficult to specifically model this disease when there is so much over lap with other psychotic disorders like bipolar, Alzheimer’s, and depression. Moore et al was able to excel at taking a bunch of different symptoms, behavioral and physiological, and showing how they all may be potentially the result of anatomical condensation of neuronal matter in the prefrontal and occipital cortices using MAM.

Moore et al showed that there were anatomical differences, specifically reduction in density of prefrontal cortex, due to MAM treatment. They were then able to show behavioral differences between different groups of cortex makeup. This allowed for the significant results of individual tests like ataxia and prepulse inhibition to be matched to brains with increased density. The timing of MAM treatment is important for the validity of this model moving forward. The treatment says something about how the temporal expression of genes during development may play a key role in schizophrenia.

 In conjunction with the prepulse inhibition, Moore also used PCP for glutamine hypofunction as a means of implicating a dopamine pathway. MAM mice were more responsive to PCP than control. Although there is still a long way to go in developing a perfect model to understand the pathophysiology of schizophrenia, Moore connected a few general psychotic behaviors to some specific anatomical and physiological mechanisms. They showed that broad deficits brought on by the MAM mice are related not only to the increased density of the prefrontal cortex and limbic areas, but also dopaminergic in nature. These two findings set the ground work for more in depth analysis of the circuits underlying the deficits produced by schizophrenia.

One thing that I found myself searching for in the paper, because they talked about it, was the steady number of neurons. I feel that adding a figure on the stereological analysis of the mice would have brought some more clarity. They just stated that the finding was not due to a difference in number of neurons and then went on to provide sufficient figures on the density differences. I think a small figure between 4 and 5, or tacked on to the end of either, would have helped show that it was only a difference in density, not number.

Kandel lab - Kellendonk et al.

The Kandel lab’s paper was completely focused on the effect of straitum D2 receptors on the PFC abnormalities relating to schizophrenia. I really liked the introduction in the paper as it applied to some of the broader questions I had about the validity of these studies. One of the bigger problems I had with (maybe understanding the impact of) the papers is that I am not completely sure how accurate the current state of the model for schizophrenia is in mice, as Schizophrenia development is very complex and not wholly understood in humans. The authors did mention that the model is one of the biggest challenges in their tests  because of the complexity in both the genetic and physiological components. (ask- are there no naturally occurring mental diseases in animals) Things such as the DISC-1 gene and decreased levels of ANK3 in the hippocampus have been linked with schizophrenia providing genetic causes, but the wide range of symptoms in schizophrenia doesn’t seem to be justified by the model described in this paper. I understand that since the continuation of the symptoms persists after switching off the transgene, with doxycycline, developemental expression causes certain symptoms but am not sure if a specific “trigger” is needed to actually start the presentation of symptoms.  The dopamine hypothesis of schizophrenia was based on the early anti-psychotics ,  DA antagonists, that worked on D2 but they usually alleviated certain positive symptoms, while having no real effect on the negative symptoms- again – bringing into question the accuracy of the animal models, again – as they mentioned, DA problems are associated with many diseases. It would also be cool to see what time the mice developed the symptoms (expressed in humans at ages 15-35), just for curiosity’s sake (not sure if the 28 days they listed as meeting criteria qualifies for this). I was happy that they discussed the D2 overexpressed mice as being a step towards building a complete endophenotypic mouse model in the discussion, as it seems to acknowledge the problems they encounter in the field as well.

The paper establishes their support for striatal D2-R’s effect on D1 in PFC, turnover and so on – what affects working memory. I am not sure why working memory is such a big deal in schizophrenia studies, as I do not see why short-term memory is being utilized as a measure of schizophrenic symptoms. Their explanation of “the cognitive deficit may reside in an imbalance in the activation of D1 receptors in the PFC “ doesn’t really make sense to me. However, the results presented in Figure 4, showing behavioral, and working memory deficientcy do establish support for their point.   I was also a little surprised by some of the results they found, for example, in Figure 3, they found that the overexpression of D2 –Rs did not change locomotion and anxiety- which I kind of expected ( parkinsons- increased DA – locomotion problems) . In Figure 6- they observed that D2 overexpression didn’t cause obvious morphological changes- which seems very interesting as that goes along with the way humans don’t express symptoms despite having morphological differences ( abnormal pyramidal neuron lining in hippocampus, larger ventricles, etc. ) . Also the changed DA transmission observed in Fig. 6C would match the problems seen in things like COMT and MAO in schizophrenic patients. Finally, although some of their data had low significances, the fact that it was approved by reviewers and that they sourced many articles talking about how D2 overexpression has been given a lot of support in the development of schizophrenia makes me think that their results are valid. They did use a lot of behavioral assays and have a lot of data, with great interpretation as well. 

Schizophrenia articles

Schizophrenia is a unique disorder where there are many possible ways of looking at the pathology and circuitry of it.  Both articles had unique ways of examining the aspects of schizophrenia. I enjoyed Moore et al.’s approach to examining schizophrenia at a developmental point, since changes in the brain could occur before birth, even though schizophrenia can be diagnosed after puberty. I would definitely be interested in reading more about these models that can be used for early detection of behavioral abnormalities.  I also thought that adding the analysis of ataxia was interesting to use for behavioral testing. It would be cool to look at ataxia models by observing cerebellar circuits in schizophrenia patients.

Kellendonk et al.  take an approach step by step observing the overexpression of D2 receptors in the striatum, which was a lot for me to understand. However, each experiment only helped me validate the use of D2 receptors, even though there was not a lot of significance in the experiments performed. These models were sufficient with getting the idea that D2 overexpression does not affect cognitive deficits as much and that even D1 receptors in the PFC are an important factor in working memory. Perhaps looking at research with just D1 receptors could help validate more things. However, as the authors mentioned in this paper, rodent model tend to cause some limitations when they are being examined. Looking at a clinical view, it’s easier to examine other positive symptoms, like hallucinations and delusions, in human models. It would be interesting to examine research done for bipolar disorder, since both schizophrenia and bipolar disorder to exhibit some similar circuitry with GABA neurons.