Rebalancing inhibition: α5 GABA_A receptor positive and negative allosteric modulation in Alzheimer's disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive and memory decline. An imbalance in the excitatory/inhibitory (E/I) neurotransmitter systems is hypothesized to play a significant role in the pathological mechanisms underlying this cognitive failure. As therapies targeting the excitatory side of this E/I balance provide only mild symptomatic relief, modulating inhibitory GABAergic neurotransmission has emerged as a potential therapeutic strategy for AD. α5 GABA type A receptors (α5-GABAARs) are of particular interest given their high expression in the hippocampus and involvement in learning and memory processes. Positive and negative allosteric modulators of α5-GABAARs have been developed with the converging aim of cognitive enhancement. This perspective explores the current literature on positive and negative allosteric modulators of α5-GABAARs in AD and proposes a model where two drug classes with opposing mechanisms can both offer therapeutic potential. Current evidence suggests that α5-GABAAR modulation may play divergent, circuit-dependent roles, such that negative allosteric modulators could enhance cognition in conditions of excessive inhibition, while positive allosteric modulators may be beneficial in hyperexcitable circuits. Ultimately, the successful clinical translation of α5-GABAAR positive and negative allosteric modulators will require careful phenotyping of neuronal activity and E/I balance to align pharmacological strategies with circuit state.