Extrasynaptic Localization Is Essential for α5GABA_A Receptor Modulation of Dopamine System Function

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting gamma-aminobutyric acid type A receptors (GABA_ARs) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that gamma-aminobutyric acid type A receptors containing the α1 subunit (α1GABA_ARs) are primarily located in the synapse, whereas gamma-aminobutyric acid type A receptors containing the α5 subunit (α5GABA_ARs) are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected an siRNA into the vHipp to knock down radixin, a scaffolding protein that holds α5GABA_ARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABA_ARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABA_A Rs from the extrasynaptic space to the synapse would prevent the effects of α5-PAM on dopamine system function. As expected, the knockdown of radixin significantly decreased radixin-associated α5GABA_ARs and increased the proportion of synaptic α5GABA_ARs, without changing the overall expression of α5GABA_ARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of α5GABA_ARs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic α5GABA_ARs; thus, efficacy may be diminished in conditions where aberrant hippocampal activity is present.