DISC1 and mGlu5 - Dana Walker


Ayhan et al. and Burrows et al. wrote articles on differing approaches to modelling schizophrenia in mice. Ayhan and colleagues’ 2011 article focused on DISC1 and how it can be a risk factor for schizophrenia based on its effects during several stages of neurodevelopment. They cited the neurodevelopmental hypothesis, which states that both prenatal and early postnatal abnormalities can contribute to the development of schizophrenia and other mood disorders. They studied whether prenatal and/or postnatal expression of mutant DISC1 would give mice symptoms reminiscent of schizophrenia. Their four experimental groups all had a mutant hDISC1 gene; the different was when it was suppressed by Dox. Table 1 contained a summary of results, and there were a few observations that stuck out. All groups (aside from controls) had fewer PV cells and decreased levels of dopamine in the male frontal cortex. The Pre+Post group showed decreased social behavior and increased aggressive behavior, while the postnatal group only showed the former and the prenatal group showed neither. Some behavioral or neuroanatomical results were seen in either pre- or postnatal groups, but not the Pre+Post group. However, no measurements were isolated to both the prenatal and the postnatal group (isolating the Pre+Post group.)
The fact that some changes (decreased DA content in female hippocampi, decreased brain volume, increased linear spine density) occurred exclusively during either prenatal or postnatal exposure (not both) is interesting. As the authors mentioned, it shows the differing but interacting effects DISC1 can have during development. They also spoke to the opposite effect: incidents where prenatal and postnatal exposure showed the same changes. Just because these two times of exposure may have had the same end results, doesn’t indicate the pathways were the same. Overall, the article speaks to the complexity of schizophrenia and the need for temporal precision when influencing gene expression in mice.
Burrows and colleagues focused on environmental factors and the theory that the glutamatergic system is implicated in the development of schizophrenia. Two particular glutamate receptors are NMDA and mGlu5. This study expanded on research on these receptors while also incorporating environmental enrichment, a paradigm shown to enhance stimulation and induce plasticity. The authors investigated the effects of EE on mice lacking mGlu5. Mice were either wildtype or mGlu5 knockouts and were given either standard or environmentally enriched housing, followed by behavioral and neurobiological tests. EE regulated some behavioral impairments in mice lacking mGlu5. It was able to ameliorate PPI and spatial learning deficits, as well as reduce spontaneous hyperactivity. However, it didn’t affect short-term memory. MK-801, an NMDAR antagonist, produced a locomotor response at a lower dosage in knockout mice than control mice. EE exacerbated these effects. This helped confirm that mGlu5 regulates NMDAR signaling.
Interestingly, there were no sex differences found in this article within any of the experimental groups. Considering Ayhan’s article cited several sex differences in behavioral changes as affected by DISC1, I expected there to also be differences in this article. Particularly, Ayhan noted decreased DA content in the female hippocampus when mice were exposed to postnatal expression of hDISC1. Burrows utilized tasks involving the hippocampus in their study and reported no differences. The hippocampus likely differs between males and females in specific ways, and it’s possible these memory tasks didn’t reflect that. However, it would be interesting to further study sex differences in the hippocampus and prefrontal cortex (the other area noted to be different in the 2011 study) and how they contribute to the complex diagnosis of schizophrenia.

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