In this study, the authors report that mice lacking the α3 subunit of the GABA-A receptor exhibit a set of abnormalities consistent with a hyperdopaminergic state. Based on this information, they suggest that agonists with activity at this subclass of GABA receptors might have antipsychotic effects without the sedation and motor side effects of existing antipsychotic medications. The study raises a number of interesting questions. First, although the α3 subunit of the GABA-A receptor is the main subtype present in dopaminergic neurons, as nicely illustrated in Figure 1A of this paper, this subunit also appears to be expressed by other neurons, such as pyramidal neurons located in the deep layers of the prefrontal cortex, whose output can influence subcortical dopamine activity. Are the observed behavioral changes in these mice mediated solely by reduced inhibitory control of dopamine neurons or via alterations in cortical output, as well?

Second, in the cerebral cortex, the α3 subunit is expressed at high levels during early development and then declines in parallel with a rise in expression of the α1 subunit. As has been demonstrated for other systems, the effects of manipulation of neurotransmitter activity at a given receptor can differ markedly depending upon the age of the animal. Does the elimination of the α3 subunit induce developmental changes to neural circuits, producing a phenotype that differs from that which would occur by inactivation of this receptor in adulthood?

Third, the therapeutic strategy suggested by the authors does not require a disease-related abnormality in the molecular target. However, given the presence of the α3 subunit in other brain regions, what are the potential effects of α3 selective agonists beyond the inhibition of dopamine neurons? Interestingly, the α3 subunit has been reported in some studies to be present in the axon initial segment of cortical pyramidal neurons, a site which we have suggested exhibits impaired inhibitory control in schizophrenia.

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