Ayhan: Time matters.

Last week Kellendonk and Moore introduced the temporal importance of development on schizophrenia. After reading those papers it appeared that there must be something going on early in development, that once initiated or created, remains latent until later on after puberty. Ayhan et al focused their paper on delving into a particular mutant protein, hDISC1. They were able to express the mutant protein at specific times during development using the DOX diet as we have previously seen. When reading the methods of the protocol, it seemed like there could be some pretty interesting results. Maybe the different temporally expressed mutant protein will show us some cool histochemical, brain imaging, or protein distributions in schizophrenia phenotype mice. But the results were rather underwhelming. Most of the significant findings were with in the PRE+POST group of mice, so these mice expressed the mutant during development and all the way through the behavioral testing and sacrifice for imaging. This was kind of like, “duh” if you express a mutant protein for that long, obviously you are going to see some significant results. I feel that the results did not do a whole lot at targeting what is going on developmentally with schizophrenic patients, they kind of just confirmed that PRE birth is important, as well as POST birth development.

These folks did something that we haven’t really seen much yet in our papers so far, by discriminating between male and female mice. Ayhan et al took a look at the gender differences, but represented there data in a weird way. In Figure 2 they bounce around between males and females depending on the test. For example, the social interaction test data was only shown for males and the FST only showed female data. This was kind of confusing because they didn’t show the contrasting data between the genders, they only showed the significant data. It was particularly interesting about these findings that there were no major differences in brain morphology or protein distribution between females and males, but there were behavioral differences found. These results really beg the question of what is it then that is creating these gender differences. We know that males and females mature at different rates, could the difference in rate of development play a role?

Burrows et al

I found it interesting that Burrows et al took a different approach to schizophrenia treatment and research. In other research papers involving schizophrenia models, most of the approaches used were targeted at the specific receptor or neurotransmitter. Burrows et al used the environment enrichment model to test out the glutamate hypothesis which I thought was interesting in comparison to previous articles where this approach was not used when looking at the effects of dopamine. Burrows et al did a good job of covering a wide range of behavioral signs present in schizophrenia in the new model. It showed future usefulness as it encompassed a wide range of symptoms. There was strong evidence for the use of this model and the glutamate hypothesis and the importance of the role NMDAR in this model. In comparison to previous articles, I found Burrows et al to be more compelling since it was able to address more parts of schizophrenia than other papers before. Another reason why Burrows et al is more compelling is due to the fact that schizophrenia symptoms can be observed in mature rats as well rather than just embryonic stages. This shows better evidence for a schizophrenia model since the onset of schizophrenia is later on in life.

                Overall Burrows et al did a comprehensive overview of this methodology and the glutamate hypothesis. But like any other research, it is not completely conclusive. I think it is heading towards the right direction of finding treatment methods by understanding the role of NMDAR and glutamate. If it were possible as a treatment method, it would have to be through monitoring these levels in humans which can control the expression of such symptoms. 

Schizophrenia 4/6/15 Papers

The idea of “nature versus nurture” is a common topic of conversation in the field of psychology. I think about it often in the context of how it’s not necessarily one aspect or the other that has the largest impact on expressed phenotypes or behaviors. I thought that the pairing of these articles worked really well together in looking at schizophrenia. While the Ayhan et al paper researched the impact of the timing of DISC1 mutations, the Burrows et al paper focused more on the effect of altering the environment in which the animals were reared. 

 It makes a lot of sense that the wild-type animals in the Burrows paper exhibited increased dendritic complexity, but it was a little disappointing to see that the knockout mice did not show any significant structural changes. I thought that both of these papers showed a decently wide range of types of techniques to validate their data, but it may have been interesting if there were more variability between subject groups.

In the Anyan paper, there were a few examples in the data which showed sexual dimorphism in relations to brain chemistry. I would be very interested to see what research comes after this knowing that some types of mental illnesses are more common in females versus males (and vice versa). In regards to schizophrenic patients, it seems like the use of therapy and behavioral modifications aren’t used as often as pharmaceuticals are. It’s interesting to think that there may be a preventative behavioral/environmental treatment for schizophrenia, but I am skeptical of how some of the data from the Burrows article could translate into the human experience. Could more studies prove that children with a genetic predisposition for schizophrenia need to be raised in a certain way to better prevent this mental illness?

Ayhan and Burrows

Both papers had some interesting findings about what factors could influence schizophrenia. Burrows was focued more on an external stimuli that impact schizophrenia, whereas Ayhan was more about internal mechanisms with gene expression, specifically through natal development. Both papers had fairly convincing data, which could indicate that multiple factors play into schizophrenia. The Burrows paper found that Environmental Enrichment helped combat the effects of schizophrenia, while the Ayhan paper found that when a gene identified with Schizophrenia is turned on in particular stages of development, it has differing effects. The most convincing effect was that of postnatal expression, which had the most symptoms of schizophrenia. I found it interesting that the Burrows paper used a glutamatergic model for schizophrenia, where we have learned about other models involving MAM and dopamine. The Ayhan paper has interesting potential, such as if we can identify this gene being passed from mother to offspring, there may be a way to deactivate the gene during postnatal development, to help prevent a schizophrenic phenotype. I would also be interested to see how an enriched environment affected the test groups in the Ayhan paper, if or how it would affect the pre-, post-, and ppp natal groups differently. The environmental enrichment paradigm shows promise to be implemented as a therapy tool, if a person can possibly change their lifestyle to be more stimulating, it may be able to help as a therapeutic intervention.

Burrows et al.

I liked Burrows et al. article and I thought the topic of environmental interactions on genes was a really interesting place to begin in looking at schizophrenia as if we know that some environmental factors influence predisposed genes then perhaps they can be avoided in humans to avoid developing schizophrenia.

I enjoyed the used of the enriching environment as a main factor in the article as we have not specifically focused on this before and I thought it was a crucial model for the paper to successfully be able to present how environment can influence genes, by showing that the enriching environment can improve mental health by allowing the animals more space and a generally more enriching environment.

I think perhaps incorporating some of these enriching environmental aspects into programs to help treat people especially people sectioned due to schizophrenic systems is crucial for treatment. Treatment facilities make me think of enclosed spaces and enclosed rooms with all white walls and an uncomfortably unhomely environment, perhaps this could be encouraging negative effects on predisposed genes and by changing surrounding environments could potentially enable a more efficient recovery space to learn to deal with schizophrenia.

I found it really interesting that the authors conducted the experiments at the age where symptoms of schizophrenia typically emerge, in the post puberty stage and I thought that was a really nice addition to their model as it is something we have seen in the previous schizophrenic papers and we have discussed that the age factor is important when looking at schizophrenia.

I preferred the Burrow et al. paper as I thought the EE model was convincing and they retrieved some really solid, consistent data relating to their glutamate hypothesis.

Ayhan et al.

Schizophrenia development and onset seems so different compared to other diseases as no one can establish foolproof reasons of how and why exactly people express it. DISC1 is one of the many new genetic factors linked under the etiology of schizophrenia. There are underlying morphological differences in the brain structure of schizophrenics, larger lateral ventricles, disorganized pyramidal neurons in hippocampus, etc. Since DISC1 is found to be important in the normal development of brain function, it provides a great place of scrutinization for abnormal development in schizophrenics. Ayhan et al. compares the effects of the gene’s disruption at different (and both) time periods- pre and post natal. Their results seem to establish and build on time-dependent disruptions (hDISC1) of the nervous system here, including decreased DA levels (last weeks papers) and paravalbumin-positive cells (supports glutamate hypothesis- reduced GABA neurons in PFC). This also goes along with their testing of NMDA antagonists along with amphetamines  as they bring out the full spectrum of schizophrenia symptoms. The use of MRI is great in showing specific structural differences in the brain.

I think looking at different time periods was also a great strategy as it allows us to understand when problems with development lead to schizophrenia. The effects of disruption shows clear differences in symptoms as wel :  Prenatal- smaller brain volume, post- asocial behavior. The biggest finding of their paper is showing that hDISC1 mutants have differential effects on the brain dependent on time of protein expression, both qualitatively and quantitatively, which is supported by enough evidence and a clear sign of the amount of work they put into this paper.

Finding genetic problems means there are possible solutions to these that reduce the activity of polymorphisms in them, treating symptoms at the same time. For example, ANK3 is also found to be linked to schizophrenia and is treated by lithium. Furthermore, disruptions in ANK3 and DISC1 are both linked to other diseases as well, such as bipolar disorder, and maybe treatments for them can by utilized for other diseases as well. 

Environmental Enrichment (Burrows et al)

Like many other neurological diseases, schizophrenia has environmental factors that play a role in the expression of its disease and Burrows et al discusses how the environmental factors can play just as much of an important role in schizophrenia as the genetic factors.

I find it fascinating that Burrows and her associates showed how big of an impact the environment has on neural function and how environmental enrichment (EE), as an animal model, was able to improve schizophrenia-related behavioral impairments, especially in mice lacking metabotropic glutamate receptor 5 (mGlu5). If EE can improve some of the behavioral impairments found in schizophrenia in both mGlu5 knockout and wild type mice, how can these findings benefit humans with this disease?

EE mice were put in a situation that improved their mental state by giving them more space and creating a more likeable environment. The idea that environmental factors can help improve these impairments in mice, similar environmental factors that causes a better mental state such as physical exercise can be viewed as a way to improve these impairments in humans.  For instance, physical exercises have been shown to help with the production of BDNF in the hippocampus of humans. Interestingly, increased protein levels of hippocampal BDNF have been seen in WT mice following EE in this paper. (Supplementary Figure 3). Perhaps providing a better mental state for these mice, through EE, can have a similar and potential benefit on humans when they engage in physical exercise, leading to improvement in memory. Strangely, they mentioned that even thought there was increased BDNF protein levels in EE WT mice, no improvement in learning or memory was found, which they tried to justify as “due to the degree of difficulty of the tasks used”. Even though increased expression of BDNF on hippocampus has been shown to induce improvement in memory and learning in another publication they referenced (Falkenberg et al, 1992).

Their data has shown an improvement in spatial learning and reduction in startle response, which are both problematic areas in patients of schizophrenia. And modulating the environment of mice caused this. One can say that the take home message of this study suggests that a better mental state caused through a better environment, or in the long haul physical exercise, can have a positive influence on those suffering from schizophrenia.

Schizophrenia day 2

I agree with Katharine in that both of the papers had clear and novel ideas to research but ended up having more questions than answers at the end. Starting with the Burrows et al. paper, I found it curious that the EE KO animals became more hyperactive with the MK-801 administration, since the idea is that there would be less hyperactivity when the animals were brought up in an enriched environment. Other than that confusion, I think that this was a great way of going about schizophrenia, as it was the first paper that looked at environmental influences. Environmental influences are always a factor, especially with something like schizophrenia that has been shown to be prevalent after the mother has taken certain drugs (not necessarily illegal either). It would be interesting to see the effects of the MK-801 on the offspring of the mothers that have exposure. I think the biggest critique I had with the paper was the lack of pictures that were mentioned. It would be interesting to see the changing brain structures since plasticity was mentioned frequently.  

            What I liked about Ayhan et al.’s paper was the use of mutant hDISC1 at various time points through development; I thought it was interesting and definitely showed some promises but like Katharine, I felt that it was hard to apply to a human perspective to every aspect as I am not sure how this could be replicated. I understand that various genes “turn on” at different points throughout development but some of the measures, such as only pre, were hard for me to grasp if that would really happen. Overall though, I felt that the pre+post and the only post were better measures for the applications, since the post seems to be the most relatable with the start of schizophrenia being later in adolescence.

Burrow et al.

The articles this week looked more closely at schizophrenia like symptoms at a developmental perspective. Burrow et al takes an interesting approach for supporting the glutamate hypothesis in schizophrenia by using the environment enrichment paradigm.  I had heard of the environment enrichment paradigm when looking an synaptic plasticity and memory enhancement, but I definitely think this was a valid model while looking more at depth for schizophrenic symptoms. It was also clear to me that the upregulations of NMDAR are only enhanced in these environments.  Burrow et al. experiments on many behavioral aspects of the environment enrichment which allows us to examine the need of the NMDAR in this paradigm. Each shows a strong significance, whether it was the behavioral test or the effects of hippocampal BDNF, only supporting that this is a positive influence for the model.  It also helps that the researchers examined the rodents at an age where these symptoms of schizophrenia would begin to develop since we’ve already observed what the effects would be like in the embryonic stages. It would, however, be interesting to compare different groups ranging at different ages of the rodents to see if there are any changes with the expression.

The article contains strong data which could ultimate help take a step further for clinical investigations in humans with these symptoms at an early age. If we were ethically able to observe the NMDA receptors by using the environment enrichment than we could possibly see some sort of mediation for the behavioral impairments of schizophrenia. If anything, if we are able to understand the use of mGlu5 and its modulation with NMDAR, then perhaps there will be otherwise to upregulate this expression for patients with schizophrenia. Also continuing research for the glutamate hypothesis could become some sort of therapeutic way for treating this disorder.

Schizophrenia week 2

This week, I found that both models of schizophrenia presented had promise, but ultimately they left me with more questions than answers.

In Ayhan et al., I thought that modulating DISC1 at different times during the lifespan was very smart. Since schizophrenia has well characterized roots in development, it made a lot of sense to me to look at the timing of mutant DISC1 expression. I thought overall this paper did a good job of re-confirming the behavioral disruptions brought on by this genetic mutation, but I had a difficult time pulling together a ‘big picture’ summary. In particular, they really lost me when they started switching between male-only and female-only analysis based on where there was significance. As I read through the paper, I decided I would give them a pass until I reached their explanation, but I was disappointed to find that they barely touched on the matter, and hadn’t provided a single potential reason for why they saw these differences. While I think it was useful to go through and identify the variability between genders, I think this made their overall model much weaker. I know that there are some sex differences in human schizophrenia expression (such as age of onset and severity), the findings in this paper seemed too random and unexplained to be mapped onto the human phenotype in any meaningful way. Because of this, I couldn’t convince myself that this model could be especially useful in future research, despite the fact that their data was very interesting.

The paper by Burrows et al. seemed much more clear to me, and I thought their model of schizophrenia was very strong. The use of environmental enrichment immediately made me hopeful for the possibility of early intervention and/or preventative treatment in humans. That being said, it seemed fairly obvious that living in a more enriching environment can have a number of beneficial outcomes, and I wasn’t sure if this was necessarily specific to schizophrenia as much as it is a general truth. Still, the ability to improve the cognitive function of mGlu5 KO mice was very promising. I think the ability to improve an animal’s function (and perhaps quality of life) in spite of genetic mutations is an important line of research.