UCSF

ApoE4 is the main genetic risk factor for Alzheimer’s disease (AD) and causes dysfunction and death in inhibitory interneurons in humans and AD mouse models. In apoE4 knock-in mice (apoE4-KI), a model of late-onset AD, replacing lost inhibitory interneurons with GABAergic progenitors restores inhibition and rescues learning and memory behavior. Postsynaptic inhibitory transmission depends on receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and on the equilibrium potential for chloride (ECl). To determine whether increasing postsynaptic inhibitory transmission – rather than replacing lost interneurons themselves – rescues learning and memory in apoE4-KI mice, we evaluated two strategies to increase postsynaptic inhibition. The diuretic drug bumetanide hyperpolarizes ECl by inhibiting the chloride importer NKCC1 in neurons. We show that aged apoE4-KI mice have increased expression of NKCC1 and that chronic treatment with bumetanide normalizes learning and memory behavior. We also show that increasing expression of GABAA receptor subunit δ in the hippocampus of aged apoE4-KI mice rescues cognitive flexibility and anxiety-like behavior, and ameliorates inhibitory interneuron losses. These results suggest that postsynaptic inhibition is an effective, druggable target for apoE4-related AD with potential disease-modifying effects.