Molecular aspects of age-related cognitive decline: the role of GABA signaling

•Prefrontal cortex and hippocampus support memory functions that decline with age.•GABA-mediated inhibition plays a crucial role in neural circuits that support memory.•Aging results in altered GABAergic signaling in prefrontal cortex and hippocampus.•Treatments that normalize GABA signaling may improve memory in aging.

Alterations in inhibitory interneurons contribute to cognitive deficits associated with several psychiatric and neurological diseases. Phasic and tonic inhibition imparted by γ-aminobutyric acid (GABA) receptors regulates neural activity and helps to establish the appropriate network dynamics in cortical circuits that support normal cognition. This review highlights basic science demonstrating that inhibitory signaling is altered in aging, and discusses the impact of age-related shifts in inhibition on different forms of memory function, including hippocampus-dependent spatial reference memory and prefrontal cortex (PFC)-dependent working memory. The clinical appropriateness and tractability of select therapeutic candidates for cognitive aging that target receptors mediating inhibition are also discussed.