Ayhan et al and Burrows et al

Last week’s papers explained mice and rat models that could be used to demonstrate schizophrenia symptoms (mostly positive). When discussing how they could improve in class, it was mentioned that these models, while sufficient in many ways, do not tackle the huge environmental factor involved in the onset of schizophrenia. One paper did address embryonic development, but mainly focused on cortical alterations before birth. This week’s papers addressed these points, as well as many other factors involved in mental illness, and because of this, these might be one of my favorite set of paper topics.

Burrows et. al. introduced an environmental enrichment paradigm in which mice were housed in larger cages with various novelty stimuli that were changed weekly, access to running wheels, and an exploratory chamber with platforms, bridges, and ropes. The paper focused on the interaction between the NMDA receptor and metabotropic glutamate receptor 5 under varying environmental conditions. To do this, they used mGlu5 knock out mice and found that these mice exhibited reduced prepulse inhibition, long-term memory deficits, and locomotor hyperactivity. Interestingly, the knock out mice exposed environmental enrichment did not display these disparities, indicating that environmental enrichment could have an effect on the NMDA/mGlu-R dysfunction related to schizophrenia. A part of the paper that seemed less definite and had not as straight forward results was when they addressed the effects of environmental enrichment on hippocampal BDNF protein levels, NMDA-R composition and Dendritic Branch Complexity knock out mice. In the discussion they mention the importance of GluN2A subunit levels and their role in experience dependent regulation of NMDA-R subunit composition. I think it would be worthwhile to expand on this point, because this could lead to a deeper molecular understanding of experience dependent diseases such as schizophrenia, as well as why experiment enrichment seems to alleviate some symptoms.

Ayhan et. al. examined the effect of mutant human DISC1 on developmental phenotypes. I personally enjoyed this paper more because it thoroughly addressed the developmental aspects by having pre, post and pre and post groups (regulating this with Dox). I also enjoyed how they included the male and female variables. I thought it was interesting that mutant DISC male mice showed more aggression, and pre+post mutant DISC females exhibited depression like phenotypes in the TST and FST tests. This starts to address how schizophrenia may look different on males versus females in terms of symptoms, and I would like to see a more extensive experiment containing tests for all symptoms of schizophrenia and comparing results between male and females with mutant DISC genes- perhaps including working memory tests or PCP/amphetamine injections? In the last set of papers, PCP showed its effects on ambulation only after puberty. It would be interesting to see the varying effects of mutant DISC gene and the after puberty, since the mice were tested when they were only 3-7 months old. Combining the two papers, I would be interested to see the effects of environmental enrichment on mutant DISC1 mice, and if the stage of development in which the mutant DISC1 was expressed changes the effect of environmental enrichment. I think this study has more clinical applications, because if we are able to understand the specificities of schizophrenia and development it could lead to earlier intervention and potential dampening of full onset schizophrenia.