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Losing Your (Prepulse) Inhibitions—All About α3 GABAA?

20 November 2005. One of the most studied endophenotypes of schizophrenia is impaired prepulse inhibition (PPI), considered to be a measure of the brain's ability to close the gate on irrelevant sensory information. In a paper published online November 11 in the PNAS Early Edition, researchers in Switzerland describe how they produced impaired prepulse inhibition in mice by knocking out the α3 GABAA receptor subunit.

Citing evidence from their earlier work that the α3 subunit is the main variant in GABAA receptors on midbrain dopaminergic neurons (Fritschy and Mohler, 1995), Hanns Mohler, Benjamin Yee, and colleagues at the University of Zurich, the Swiss Federal Institute of Technology, Zurich, and several other institutions reasoned that knocking out this subunit would release dopaminergic neurons from inhibitory GABAergic control. The subsequent hyperactivity of the DA neurons might then mimic the hyperdopaminergic state of cortical regions in schizophrenia, presumed to underlie deficits in PPI.

The knockout was accomplished by duplicating exon 4, which was shown by Western blot and immunohistochemistry to abolish expression of the α3 subunit. There was no detected compensatory upregulation of other GABAA receptor subunits. And since these other subunits make up the bulk of GABAA receptors in parts of the brain other than the midbrain, the mutant mice were able to develop to adulthood without overt behavioral or morphological abnormalities.

To examine more subtle effects of the α3 gene knockout, Yee and colleagues spritzed GABA onto midbrain slice sections containing dopaminergic neurons. In sections from normal brain, this generates an inhibitory current (in this experiment, 98.2 +/- 7.6 pA, n = 5), but in slices from α3 knockout mice, these inhibitory currents were significantly reduced (43.4 +/- 7.7 pA, n = 8; P <0.05). This remaining inhibitory response is presumably mediated by GABAA receptors containing other subunits.

The notable behavioral correlate to this physiological phenomenon was a significant deficit in prepulse inhibition. This deficit is seen in patients with schizophrenia, and is seen as evidence for problems in sensory gating (though it may also reflect deficits in working memory). In their study, Yee and colleagues found that mice lacking the α3 GABAA subunit were unable to respond normally to paired auditory stimuli. Whereas wild-type mice do not startle as easily to a loud noise if they have just heard a softer tone (prepulse), the mutant mice showed a significantly elevated startle response to the second tone, compared to the wild-type mice. This was not a sensory deficit, since both types of mice responded equally to a loud tone without a prepulse.

"The further demonstration that this deficiency could be normalized by the D2-receptor antagonist haloperidol at a dose that was insufficient to affect performance in WT controls indicates that the sensorimotor-gating deficit in the α3 knockout mice is dopamine-dependent, strengthening the view that the deficit in PPI in the α3 knockout mice stems primarily from a disinhibition of mesolimbic dopamine neurons," contend the authors.

On the other hand, although the α3 knockout mice were slightly, but significantly, more active than their normal relatives, they had an equivalent activity increase in response to amphetamine. This further supports the validity of these mice as models for PPI in schizophrenia, the authors argue, since patients show a normal amphetamine-induced dopamine release. The α3 knockout mice also had normal responses to anxiety challenges and to the anxiolytic drug diazepam, which targets α2 GABAA subunits.

Yee and colleagues do not address whether the manipulation has effects on other systems that are modulated by α3-containing GABAA receptors, such as forebrain cholinergic projections, or the other brainstem monoaminergic systems (Fritschy and Mohler, 1995; Rodriguez-Pallares et al., 2001). However, the present results would suggest that "α3-containing GABAA receptors may serve as valuable targets for antipsychotics that would be expected to be nonsedating and free of the extrapyramidal subunits," they write.—Hakon Heimer.

Reference:
Yee BK, Keist R, von Boehmer L, Studer R, Benke D, Hagenbuch N, Dong Y, Malenka RC, Fritschy J-M, Bluethmann H, Feldon J, Mohler H, Rudolph U. A schizophrenia-related sensorimotor deficit links alpha3-containing GABAA receptors to a dopamine hyperfunction. PNAS Early Edition. Abstract

Comments on News and Primary Papers
Comment by:  David Lewis, SRF Advisor
Submitted 18 November 2005
Posted 18 November 2005

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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