Title:Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance
Volume: 16
Issue: 7
Author(s): Ming Shiuan Soh and Joseph W. Lynch
Affiliation:
Keywords:
Allosteric modulator, alpha5 GABAA receptor, Alzheimer, amnesia, down syndrome, memory impairment,
nootropic, stroke.
Abstract: GABAA receptors containing the α5 subunit (α5GABAARs) are found mainly in the hippocampus
where they mediate a tonic chloride leak current and contribute a slow component to
GABAergic inhibitory synaptic currents. Their inhibitory effect on the excitability of hippocampal
neurons at least partly explains why changes in the level of activity of α5GABAARs affect cognition,
learning and memory. These receptors have been implicated as potential therapeutic targets for a range
of clinical conditions including age-related dementia, stroke, schizophrenia, Down syndrome and anesthetic-
induced amnesia. Accordingly, a range of pharmacological modulators that selectively target
α5GABAARs, as either inhibitors or allosteric enhancers, have been developed. Although many of these compounds show
therapeutic effects in animal models of the above clinical disorders, none has been marketed yet due to unsuccessful clinical
trials and toxicity in humans. These experiments have also revealed paradoxical effects of α5GABAAR modulation
(e.g., cognitive impairments can be reversed by both positive and negative modulation), suggesting that our knowledge of
the physiological roles of α5GABAARs is incomplete. This review highlights the various positive and negative modulators
for α5GABAARs that have been developed, key findings concerning their effects in behavioral studies, and their importance
across a number of therapeutic fields. It also highlights some of the gaps in our knowledge of the physiological and
pathological roles of α5GABAARs.
