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.