Sunday, March 12, 2017

Kellendonk & Moore

The question in the Kellendonk paper asks what the behavioral and physiological consequences of increased D2 receptor function is in the rodent striatum. However, based on previous research, we already basically know what will happen when we increase D2R function in the rodent striatum – what we really want to know from this paper is how doing this will fit into the various hypotheses regarding the origin of DA dysfunction and its consequences in the schizophrenic brain.
While most of the paper was spent proving that the outcome of the manipulations on D2 transgenic mice worked/was what they expected it to be, the important findings (in my opinion) were that the cognitive deficits were not reversible along with D2 receptor hyperfunction in the striatum, plus the incurrence of compensation in mPFC D1 receptor function. Results suggest bidirectionality in the system and offer two possible explanations for the homeostatic mechanism apparent between D2 receptors in the subcortex and cortical D1.
This paper is awesome for paving the way for future study, but I do disagree with the last line; I don’t think that we can extrapolate from these results that this study has achieved confirmation of causality (ie, that D2 receptor gene polymorphism causes D2R dysfunction which causes D1R compensation).
The Moore paper is more extensive as a model of schizophrenia than the Kellendonk paper, but each has problems – in this model, all pathology “boxes” are checked, but the mechanism of MAM methylation on E17 is not explored. Testing what developmental processes occur on that day shouldn’t be hard in a rodent model. But that seems to me the right next step for this research.

This model tackles the DA problem at an interesting angle (hyperresponse to psychoactive drugs) but is na├»ve to the subtleties of the DA receptor balance that the Kellendonk paper examined. The Moore model doesn’t rule out the validity of the Kellendonk model, especially when considering the possibility that a DAR polymorphism is responsible for DAR dysfunction – perhaps this is a development on E17?

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