I really appreciated the fact that the Ayhan et al study used both male and female mice, highlighting sex differences in response to manipulation of mutant DISC1 expression. Many of the experiments in the this paper clearly show phenotypic sex-differences that would otherwise be overlooked had they not taken this approach, an important consideration considering the documented sex differences seen in human schizophrenic patients. The FST and TST results in which pre-post females showed a phenotype were interesting due to the fact that depression, and schizophrenia, is more common in women. The results that show male mice are more responsive to the hyper locomotor effects of MK-801 and D-amphetamine were also of interest as it may suggest that men with schizophrenia are more prone to exhibit psychosis-like behaviors since the authors list this as the reciprocal response to amphetamine and N-methyl-D-aspartic acid antagonists in humans. I was surprised that they saw differences in the post and pre+post groups because a phenotype in the post group should also result in a change in the pre+post group by default. However, the pre-post phenotypes appear to be trending towards the post phenotypes in figures 2d and 3c, even if it is not significant.
The exploration of both environmental and genetic factors and how those, in combination, modulate schizophrenia like phenotypes seemed like a huge undertaking but the defined and controlled experimental manipulations made in the Burrows et al paper appeared to make such a difficult question simpler to address. It is clear that the environmental enrichment condition serves to ameliorate the impaired behavioral performance of the mGlu5 knockout mice, and though this does not necessitate that there is an interaction between the genetics and environmental conditions, the citation stating that environmental enrichment has been shown to up regulate expression of NMDAR, another glutamate receptor, serves as evidence that there may be some interesting interactions between the EE condition and glutamate receptor expression/activity that may mediate schizophrenia-like phenotypes. Clearly the ameliorating effects of environmental enrichment are not acting purely through the mGlu5 receptor, if at all, since the phenotype improvement can happen in the mGlu5 KO mice. With this in mind, I would be interested to see if there would be a similar phenotype in an NMDAR KO or in a double KO of both types of receptors, if it is possible to have living mice with both receptors knocked out. It would also be interesting to see if there were converse and complementary behavioral and molecular results when comparing KO SH mice with KO mice in an impoverished environment.