Sunday, October 30, 2016

Complexities in Modeling Schizophrenia

To begin, I want to talk about the two theories/ hypotheses behind the etiology of schizophrenia. Schizophrenia symptoms are typically categorized into three categories as follows: Positive (hallucinations, delusions, disordered thoughts), Negative (flat affect, reduced pleasure in activities, reduced speaking), and Cognitive (poor executive functioning, problems with working memory, trouble focusing). The two main theories of schizophrenia focus on the malfunctioning of two different neurotransmitter systems to explain the various symptoms implicated in schizophrenia. 

The Dopamine Hypothesis came into view in the 1970s after scientists observed that the psychosis caused by amphetamine drugs was similar to the positive symptoms of schizophrenia. These drugs are dopamine receptor (D2) agonists. A class of drugs now known as anti-psychotics were found to be helpful in relieving positive symptoms by taking a reverse action and antagonizing D2 receptors. Unfortunately, these drugs do almost nothing to alleviate the negative symptoms of schizophrenia, implying that the etiology of the disease is much more complicated than an increase of dopamine activity. 

The Glutamate Hypothesis emerged in the 1980s after scientists observed that the effects of NDMA antagonist drugs like PCP and ketamine can be similar to the symptoms of schizophrenia. It is possible that the activity at this receptor can cause a wider variety of schizophrenia symptoms via interactions with dopamine and GABA. So far, there has been mixed results in new treatments that involve an NDMA agonist.

  I found the difference in approach between the two papers to be particularly interesting this week since one paper embraced both the dopamine and glutamate hypotheses and the other paper focused on the dopamine hypothesis alone. 

The Moore et al paper seeks to create a model of schizophrenia by disrupting brain development at an important time point to create reduced brain volumes in areas specific to schizophrenia. Although this model seems viable, it requires much further testing from this initial study. Moore et al has sufficiently shown that this model behaviorally looks like schizophrenia, but they have done minimal investigation about the model's effects on neurotransmitter activity. They do include some experiments with both PCP and amphetamine to show that MAM E17 rats have and elevated response to both drugs. This implies that their model has developmentally altered the glutamate and dopamine pathways, however, more exploration is needed in this area. They could have stained for TH (a enzyme vital to making dopamine) or NDMA receptors to examine the specific alterations that MAM causes over the course of development to see if these changes are analogous to changes seen in post mortem brains of humans with schizophrenia.

Alternatively, the Kellendonk et al paper focused on a model that only concerned the dopamine hypothesis and transgenically altered the expression of D2 receptors in the striatum. This paper outlines some of the major issues that come with models of schizophrenia that only focus on the dopamine hypothesis. This model does demonstrate that a developmental change in D2 expression causes long-lasting changes in cognitive function, even after the restoration of normal D2 expression. It would be interesting to see if this developmental change has significant effects on other neurotransmitter pathways- primarily glutamate and NDMA receptors. 

Regardless of the approach to modeling schizophrenia in animals, great care must be taken to avoid over-anthropomorphizing lab animals. It can become very easy to interpret animal behavior as an emotionally analogous to humans. However, it is important to remember that despite many genetic similarities, humans are still very different from rodents. It is impossible to ask mice and rats if they are hallucinating or having delusions of grandeur, or even to know if rodents can experience such things. Therefore any models that are created will have to be researched with a grain of salt.

No comments:

Post a Comment