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 α5 GABA A receptor offers a promising therapeutic strategy to mitigate the impairment of 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 the 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.
• α5IA improved β-amyloid-induced impaired LTP in the hippocampal CA1 pyramidal layer
• α5IA reduced β-amyloid-induced elevated tonic conductance in the CA1 hippocampal pyramidal neurons
• α5IA restored β-amyloid-induced long-term spatial memory deficits
• α5 GABA type A receptors are promising targets for Alzheimer’s disease therapies