D2

Transgenic mice are designed to test a specific hypothesis, but the results are sometimes unexpected. In the striatum, there are abundant dopamine receptors, of D1 and D2 subtype. Which phenotype should transgenic mice that over-express D2 dopamine receptors have?

A recent article published in Neuron by the group of Kandel (Kellendonk et al., 2006) reports transgenic mice that overexpress D2 dopamine receptors. The expression is regulated by tetracycline (This means that the gene can be switched off by adding doxycycline.), and restricted to the striatum.

The mice have normal locomotor activity as well as anxiety levels. Based on our understanding of the striatum, these results are unexpected. The only deficits that the authors did find, however, are difficulties with working memory tasks, and lack of behavioural flexibility.

The authors switched off the gene with doxycycline, but the working memory did not improve, even if the gene is switched off at birth. They conclude that the deficits may be due to a “chronic or developmental expression of the receptors.” Another alternative would be that doxycycline does not switch off the gene completely, and a basal activity of the gene would generate sufficient receptors to account for the deficits. One way to check this possibility would be to measure the receptor binding in mice treated with doxycycline. Another possibility is a developmental defect, that is the overexpression of D2 receptors affect the wiring of neurones. A way to check for that would be to treat the mice with doxycycline in utero.