The β-amyloid-induced increased tonic conductance, impaired long-term potentiation and cognitive deficits characteristic of Alzheimer's disease are reversed by an α5 inverse agonist of the GABA type A receptor

O'Connell, Aoife, Calvo-Flores Guzmán, Beatriz, Zhai, Ying, Keighron, Cameron N., Boix, Jordi, Peppercorn, Katie, Tate, Warren P., Waldvogel, Henry J., Faull, Richard L. M., Montgomery, Johanna M., Quinlan, Leo, Kwakowsky, Andrea. (2026). The β-amyloid-induced increased tonic conductance, impaired long-term potentiation and cognitive deficits characteristic of Alzheimer's disease are reversed by an α5 inverse agonist of the GABA type A receptor. Neuropharmacology, 290, https://doi.org/10.1016/j.neuropharm.2026.110892

Abstract

Alzheimer's disease is a chronic, progressive neurodegenerative disorder characterized by cognitive impairment, which may arise from disruptions in the excitatory/inhibitory balance within the brain. Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the central nervous system, plays a crucial role in maintaining the excitatory/inhibitory balance and regulating neuronal activity involved in memory. In Alzheimer's disease, changes in α5 GABA A type receptor expression and activity increase tonic inhibition, disturbing the neuronal excitatory/inhibitory balance and ultimately impairing cognitive processes. Therefore, targeting the α5 GABA A receptor offers a promising therapeutic strategy to mitigate impairments in these processes. This study examined the potential of an α5 GABA A receptor-selective inverse agonist, α5IA, for treating β-amyloid-induced cognitive deficits and the underlying mechanism of action, using ex vivo microelectrode array and patch clamp electrophysiology. The inverse agonist, α5IA, improved impaired long-term potentiation, reduced elevated tonic conductance in CA1 hippocampal neurons and improved long-term spatial memory deficits induced by β-amyloid. These findings highlight α5IA's ability to restore excitatory/inhibitory balance and, thereby, cognitive function. The selective targeting of α5 GABA type A receptors with α5 GABA A receptor inverse agonists, such as α5IA, represents a promising direction for developing novel Alzheimer's disease therapies.

Funder

University of Galway
Alzheimers New Zealand
Freemasons New Zealand
Alzheimers New Zealand Charitable Trust
Aotearoa Foundation, New Zealand
Health Research Council of New Zealand
Otago Medical School
Department of Physiology, University of Otago

Publisher

Elsevier

Rights

CC BY

cb

Collections

Publications