Ayhan et al vs Burrows et al
Seminar in BioPsych
Reading these two papers brought something to my attention that I remember being told during my first co-op, and I suppose I hadn’t thought about it thoroughly until now. During my first co-op, the post-doc I worked under once told me that he would never use mouse behavior to study complex mental disorders because it is inherently difficult to create an animal correlate of, say, schizophrenia (he was using electrophysiological techniques to understand how the brain processes innate olfactory valence). I shelved the idea until we delved into our readings about schizophrenia. Last week, and even more so this week, I’ve come to realize that these experiments using mouse models to probe the workings of schizophrenia are simply a small manipulation followed by a selection of tests (behavioral, histological, functional, etc.) to validate the small manipulation. The issue is that there is no standard for tests (each paper contains — in my eyes — an arbitrary selection of tests to attempt to validate the translatability of this model. Furthermore, the interpretations can get iffy because of the vast amount of things that are affected by the manipulation. Here’s what I mean:
Ayhan et al addressed the issue of introducing developmental abnormality to create a model for schizophrenia. It had been known previously that postnatal expression of DISC1 leads to developmental abnormalities resembling schizophrenia, but prenatal expression of DISC1 had not been addressed. While they successfully showed that expression during both time points leads to schizophrenic-like behavior (whatever that means), they did not address the comparability of Pre+Post vs Post groups. In many of the tests, they showed that these two groups showed significantly different responses than just the Pre group or the control did. But for some of the tests, the Pre+Post group was significantly different than the Pre group, indicating that something is going on when DISC1 is expressed during the prenatal period. It could be fruitful to delve deeper into the difference between these two groups. I also found it interesting that while DA levels were considerably lower in all groups exposed to DISC1 expression, DA turnover was not affected (as indicated by comparable DA/DOPAC ratios compared to control). In general, I’m not sure how much insight this paper provided.
Burrows et al, however, I thought was very interesting because it showed that a transgenic mouse that lacked a crucial receptor could show an amelioration in symptomatology with just a fuller and more eventful life. I’ve seen in the past environmental enrichment can have a plethora of positive effects, including neurogenesis and sociability. It was awesome to see that this could occur despite these mice lacking a receptor that’s been implicated in schizophrenia (is mGlu5 dysfunction sufficient to cause schizophrenia? who knows). While I thought it was great that they addressed the issue of male and female differences, I thought that this led to a difficulty to pinpoint definitive interpretations because there were so many groups and each test showed a different selection of groups responding. For example, let’s look at the prepulse inhibition test: there were four groups (SH WT, EE WT, SH KO, EE KO), and 2 sexes (males and females) and two frequencies (30ms ISI and 100ms ISI) — so 16 groups. There were no interactions at all for the 100ms groups, so just 8 groups. For the memory tasks, the mice showed better memory in the Morris water maze but not in the Y-maze (what does that mean? who knows). Moreover, the sex differences were not deeply discussed — just that there may be some differences between the two.
I’m not completely sold by these sets of experiments, but I also must admit that tracking down the etiology of such a complex mental disorder is a gargantuan task and many scientists have made valiant attempts at addressing it.