GABA from reactive astrocytes impairs learning and memory in Alzheimer disease

Abstract

In Alzheimer disease, memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the original findings by Dr. Alzheimer, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA, by monoamine oxidase-B (Maob), and abnormally release the GABA through Best1 channel. In the dentate gyrus of mouse models of Alzheimer disease, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory. In the postmortem brain of individuals with Alzheimer disease, astrocytic GABA and MAOB are significantly up-regulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in Alzheimer disease.