Schizophrenia and Cognitive Deficits

That over-expression of D2 receptors in the striatum would cause cognitive deficits related to expression of receptors during the developmental time line, rather than consistent dopamine elevated release, is a fascinating point. I had always been interested in the comparative effects between either increasing concentration of a neurotransmitter or increasing the concentration of receptors for a neurotransmitter and leaving its basal concentration the same. On the one hand, you have more bioavailability to reach receptor targets, while on the other hand you have greater surface area distribution of receptors that can cause activation. One might assume that the results of these processes are the same, and yet the Kellendonk paper shows that there is indeed a difference between the two.

Perhaps the very reason that classical antipsychotics, which are D2 receptor antagonists, display only moderate effectiveness, is because schizophrenics already have such a high distribution of dopamine receptors in the striatum, and you can only block so many before negative side effects begin to reach lethal doses or at least very severely damaging ones. Perhaps future gene therapy will focus on decreasing copy number of the D2R gene in humans, or introduce a genetic construct that increases down regulation of D2 receptors in the striatum through kinase-driven enzymatic chain reactions.

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