Another two models for Schizophrenia in mice: mGlu5 KO and DISC1 mutant- Sierra Smith

The two papers we explored for this week, Ayhan et al and Burrows et al, took two very different approaches for modeling schizophrenia, and each of these two methods were different again from the previous schizophrenia mouse models we have seen to date. I believe this truly speaks to the complexity of modeling schizophrenia in rodents and how little we still know as a community about the exact molecular underlying of schizophrenia.

I quite immediately took a preference to the research done by the Ayhan group, which focused on using a mutant DISC1 model regulated by a system we are already familiar with: Tet-off. It was theorized by this research group that when expression of the mutant form of DISC1 was on (when the animals were being fed normal food to maintain mutant gene expression), this mutant form would bind to endogenous DISC1 and negatively regulate it in a dominant matter, rendering the protein nonfunctional. There were many things I liked about the research presented in this paper, including how thoroughly the group examined sex differences in both behavioral and molecular phenotypes of not only schizophrenia, but of other mood disorders as well under this model. It was fantastic to see such a wide variety of data presented, including thorough behavioral modeling, western blot expression analysis of both the mutant DISC1, native DISC1, and two other interacting proteins: LIS1 and NDEL1. Although Ayhan did not obtain significant results in all tests for both pre-natal and post-natally mutant DISC1 expressing groups, they gained a hugely valuable amount of insight into how sex differences play a role in this model of schizophrenia, how interruptions in DISC1, implicated in brain development and adult brain function, can cause differential effects based on whether the interruptions were pre or post natal, and how DISC1 may interact with DA and GABA signaling in different areas of the brain. One thing that perplexed me from this paper were the results obtained from analyzing dendritic spine density in DISC1 deficient mice. In all groups showing significance, dendritic spine density was actually increased when mutant DISC1 was being expressed, which goes against all other results I have read related to schizophrenia being correlated with decreased spine density in both humans and rodents.

Lastly, regarding the Burrows et al paper, I felt that much of the data obtained and published was inconclusive, although their mGlu5 KO model was a very interesting approach considering the implication of altered glutamatergic signaling in schizophrenia patients. I felt that it was a bit strange how the group tried to blame their insignificant results in the Morris Water Maze by observing two of their WT mice "switch search strategies", skewing their control data. This didn't strike me as being a great scientific explanation, and I suspect there could have been some other reason why both of these mice "switched strategies". I would like to see this specific result repeated in its entirety and with larger sample sizes.

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