Conclusion
In summary, using a multi-disciplinary approach, we have developed a novel, selective negative allosteric modulator for α5 GABAARs and characterised its effects on hippocampal dis-inhibition in a well-established mouse model of AD. We have shown that this modulator can “normalise” abnormal, inhibitory synaptic activity received by CR interneurons in this model, suggesting initially its’ therapeutic potential. Furthermore, our data provides evidence that α5 GABAARs are also preserved in other types of interneurons, such as CCK, SST and CR interneurons.
Since our data suggest that α5 GABAARs are widely expressed by both dysfunctional and resilient neurons, and also that α5-SOP002 can compromise further the aberrant hyperexcitable network in the AD model, we propose that pharmacological modulation of α5 subunit-containing GABAAR networks may not be a suitable therapeutic target for cognitive impairment in AD. Although the evidence suggests an overall improvement of memory with GABAA α5 inverse agonists in rodents, it is yet to be established what kind of short- and long-term effects these compounds might have in patients. We propose that the lack of specificity and efficacy in clinical trials could be at least in part due to a wide expression of α5 GABAARs in the hippocampus, both by various types of interneurons and pyramidal cells. Thus, targeting the α5 subunit with NAMs would result in a global effect on the hippocampal networks and would lack the specificity required to restore the complex network alteration during pathogenesis of AD that leads to the observed excitatory-inhibitory imbalance.