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Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABAA receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9-11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic.

Enhancing GABA Signaling during Middle Adulthood Prevents Age-Dependent GABAergic Interneuron Decline and Learning and Memory Deficits in ApoE4 Mice