Extrasynaptic localization is essential for α5GABAA receptor modulation of dopamine system function

Alexandra M McCoy; Thomas D Prevot; Md Yeunus Mian; Dishary Sharmin; Adeeba N Ahmad; James M Cook; Etienne L Sibille; Daniel J Lodge

doi:10.1523/ENEURO.0344-23.2023

Extrasynaptic localization is essential for α5GABA_A receptor modulation of dopamine system function

eNeuro. 2024 Feb 27;11(3):ENEURO.0344-23.2023. doi: 10.1523/ENEURO.0344-23.2023. Online ahead of print.

Authors

Alexandra M McCoy^{1

2}, Thomas D Prevot^{3

4}, Md Yeunus Mian⁵, Dishary Sharmin⁵, Adeeba N Ahmad⁶, James M Cook⁵, Etienne L Sibille^{3

4

7}, Daniel J Lodge^{1

2}

Affiliations

¹ Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX, USA.
² South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA, 78229.
³ Campbell Family Mental Health Research Institute of CAMH, Toronto, ON, Canada.
⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁵ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
⁶ University of Texas, Rio Grande Valley, Edinburg, TX, USA.
⁷ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.

Abstract

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABA_AR) 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 α1GABA_ARs are primarily located in the synapse, whereas α5GABA_ARs 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 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_ARs 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 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.Significance Statement 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.

Abstract

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