March 9 Papers: Ayhan et. al, Burrows et. al
The Disrupted In Schizophrenia 1 (DISC1) gene plays a role in both brain development and in adult brain function by helping carry out activities such as neurogenesis, neuronal migration, and dendrite maturation. However, past research has shown that mutations in this gene are a significant risk factor for the development of schizophrenia and some mood disorders. Ayhan et al’s 2011 study examined the varying neurobehavioral effects that the mutant protein hDISC1 has on mice at different stages in development. They investigated the roles hDISC1 played when expressed only during prenatal development, only during a postnatal period, or when expressed both pre- and postnatally. Their results found that the effects of hDISC1 vary widely depending on when in neurodevelopment the protein is expressed, with the most significant effects being observed when the mutant is expressed both prenatally and postnatally.
I found this paper to be very interesting as it discussed many topics and trends that I have been studying in another class I am taking this semester, Developmental Neurobiology. The main trend noted in this paper that we have repeatedly discussed in that class is that the specific timing of gene expression can lead to widely varying developmental outcomes. Another point of discussion in this paper that tied neatly into what I have been studying was the speculation that prenatal expression of hDISC1 led to decreased total brain volume because hDISC1 acts through dominant-negative mechanisms to affect proliferation of neuronal progenitor cells. Although this paper did not go further in depth about this, in my Developmental Neurobiology class we learned that one way in which cell proliferation can be slowed down is by upregulation of p27, an inhibitor that stops the progression of the cell cycle by blocking cdk, which is an enzyme that signals when a cell is ready to move to the next stage of the cell cycle. It would have been interesting if the Ayhan paper elaborated on the mechanisms by which hDISC1 could affect proliferation of neuronal progenitor cells, and it made me wonder whether it was through interactions with p27 and cdk or through other processes altogether. The fact that the paper only speculated that this might be the reason for reduced brain volume in mice that expressed hDISC1 prenatally suggests that they are not certain that this is the case, so it could also be an intriguing direction in which to take future research.
Furthermore, in my Developmental Neurobiology class we also learned that concentration gradients of different transcription factors in neural progenitor cells help determine what those cells will differentiate into later. For instance, Retinoic Acid (RA) inhibits the development of anterior structures and enhances the development of posterior structures, so low concentrations of RA in neural stem cells in the head are necessary, or else a developing embryo can end up with brain structures that are too small. Upon reading that prenatal expression of hDISC1 reduces overall brain volume, I was curious to know whether this mutant acts in a similar fashion to RA and whether the mechanisms by which it affects neural progenitor proliferation to reduce brain volume are dependent on similar concentration gradients.
It was also gratifying to read that Ayhan’s study used both male and female mice, which stands in contrast to some of the other papers we have read in this class but is important for the thoroughness and validity of research, especially if therapeutic treatments will be developed based on this research that will be applied to patients of both sexes. On a different note, the paper stated that the transgenic mice “exhibited the behavioral alterations reminiscent of aspects of both schizophrenia and mood disorders”, but two of the most prominent symptoms of schizophrenia are hallucinations and delusions, and it would be difficult to know whether mice are experiencing these symptoms as they cannot verbally communicate with the experimenters. This made me wonder if there are any experimental paradigms or tests that could give us an insight into the potential experience of psychosis-related symptoms in animals.
Moreover, previous research has suggested that deficiencies in glutamatergic signalling might be behind the development of symptoms of schizophrenia. The Burrows et al 2015 paper studied the role of metabotropic glutamate receptor 5 (mGlu5) in environmental modulation of behavioral impairments associated with schizophrenia. They did this by comparing mGlu5 KO mice exposed to an Enriched Environment (EE) to those raised under normal conditions. Their results found that the EE paradigm improved long-term spatial learning and prepulse inhibition (PPI) deficits and decreased spontaneous hyperactivity in mGlu5 KO mice. Additionally, mice exposed to the EE paradigm had different behavioral responses to the NMDAR antagonist MK-801, which suggests the beneficial behavioral outcomes of this paradigm occur as a result of changes in NMDAR signalling.
It was fascinating to read about these two completely different approaches to studying schizophrenia, one based on neurodevelopment, genetic risk, and mutations, and the other on glutamate signalling and environmental factors. This illustrates the multifaceted nature of schizophrenia and mental illnesses in general, as it is almost certain that neurodevelopmental, genetic, environmental, and intracellular signalling factors are all involved in the expression of clinical symptoms. Perhaps it could be interesting to combine these experimental approaches to studying this illness by looking at any potential changes in glutamate signalling at different stages in pre- and postnatal development and whether these are linked to the emergence of symptoms. Other potential experiments could further investigate whether being raised in an enriched environment protects against the expression of DISC1 mutations specifically, or whether there is any relationship between glutamate signalling deficits and expression of DISC1 mutations or vice versa. Overall, despite approaching the issue from different angles, both of these studies have the potential to lead to the development of new therapeutic treatments for schizophrenia.
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