Ayhan et al and Burrows et al both explore Schizophrenic mouse models, but focus on different aspects of the disease. While Ayhan et al is interested in the genetic basis and time-dependent effects of gene activation, Burrows et al questions the role of environment on glutamatergic signaling.
I thought Ayhan et al’s paper proposed a relevant model for Schizophrenia with a focus of the human Disrupted-In-Schizophrenia-1 (hDISC-1) gene in both male and female mice. First, I would like to address that idea that the researchers focused on hDISC1 which varies from mouse endogenous DISC1. This was a nuanced, but interesting, differentiation, and led to the study proposing hDISC1 mechanism of action working on and affecting the mouse endogenous DISC1. I understand that they chose the human variant to make effective conclusions and relate this to the proposed Scottish family with that specific mutation, but I would have also liked to see the role of endogenous DISC1. Another aspect that I loved about this paper was that they utilized both male and female mice. The male and female groups had slight variations; under MK-801 conditions, only male mice showed significant locomotor differences, and only females showed significant dopamine differences in the hippocampus. That being said, some data was pooled because there was not enough of a difference in results. Studying both sexes is important because not only should females be included in the narrative if we are modelling the population, but there are sex differences in schizophrenia. Females present with symptoms on average later than men. Could some of the differences observed in Ayhan’s study contribute to the sex differences seen in humans? Further studies would need to be conducted, and a mouse model may not be able to fully capture complexities, but it would be interesting to examine. Lastly, this paper focuses the timing of genes and effects in the progression of the disease, concluding that a combination of pre- and post- natal activated hDISC1 mutations contributes the most to symptoms. Recently, research has been going in the direction of early detection/diagnosis of schizophrenia, tracing the disease back to the womb. Influenza during pregnancy has even been indicated as a potential influence in developing Schizophrenia. Ayhan et al captures the idea that individuals may be predisposed Schizophrenia due to genetic mutations predating the onset of the disease by decades in the womb and right after birth. While this may not be as applicable for treatments of the disease as genetic modifying agents are morally questionable in humans, it helps the scientific community understand the disease and its mechanisms.
Burrow’s et al more primarily highlights the role of glutamatergic signaling in schizophrenia and its symptoms. mGlu5 glutamate receptors are knocked out in mice, and a series of behavioral tests and protein synthesis are used to determine if this is an effective model and if environmental influences can ameliorate the initial symptoms. While the findings of this study indicate that environmental enrichment reduces ‘symptoms’ of schizophrenia, I had trouble seeing the mGlu5 KO mice as an effective model for schizophrenia. I believe that the glutamate receptor is responsible and covers many functions that may contribute to schizophrenia, but do not capture the disease. The paper points out that many of their studies may be due to the NMDA’s and glutamate’s receptors roles in long term potentiation (LTP). If we examine the tests they use to test behavior, many of them would be improved by LTP. The Y Maze and Morris Water Maze were used to test cognition, both of which would be improved by LTP and learning, not necessarily mediating a potential mechanism disrupted in schizophrenia. That being said, if it improves symptoms, it could still help in treatment regardless of the mechanism. It is just not specific enough to schizophrenia itself - the glutamate receptors could play a variety of roles in many illnesses. That being said, enriched environments have been shown to be more beneficial in a host of diseases and disorders. In humans, having a higher education and being exposed to arts and learning, have been shown to have a protective effect against Alzheimer’s, creating a reserve that may protect an individual. This study, to me, is another example of this, but the model is not specific enough to schizophrenia. However, if enriched environments helps ameliorate potential symptoms of schizophrenia, this would have important therapeutic implications. A measure that I did conceptualize as more schizophrenia specific was the PPI (pre-pulse inhibition) which has been shown to be reduced in patients with schizophrenia. It was interesting that enriched environments improved mice PPI, indicating that it could be beneficial in treatment for schizophrenia.
Overall, both articles brought to light important concepts in Schizophrenia; genetic timing, and environmental interactions. Both play an important role in the progression of the disease, and both could be potential therapeutic targets.
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