Extrasynaptic localization is essential for α5GABA 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 (GABAR) 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 α1GABARs are primarily located in the synapse, whereas α5GABARs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds α5GABARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABARs from the extrasynaptic space to the synapse would prevent the effects of α5-PAM on dopamine system function. As expected, knockdown of radixin significantly decreased radixin-associated α5GABARs and increased the proportion of synaptic α5GABARs, without changing the overall expression of α5GABARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of α5GABARs 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 α5GABARs, thus efficacy may be diminished in conditions where aberrant hippocampal activity is present. Currently available treatments for psychosis, a debilitating symptom linked with several brain disorders, are inadequate. While they can help manage symptoms in some patients, they do so imperfectly. They are also associated with severe side effects that can cause discontinuation of medication. This study provides preclinical evidence that the drug, GL-II-73, possesses the ability to modulate dopamine activity, a key player in psychosis symptoms, and further provides some mechanistic details regarding these effects. Overall, this work contributes to the growing body of literature suggesting that GL-II-73 and similar compounds may possess antipsychotic efficacy.