![]() Aging-related memory deficits, which are exaggerated in individuals with Alzheimer's disease (AD), may result from excitatory–inhibitory imbalance of the hippocampal dentate gyrus due to inhibitory interneuron dysfunction or loss ( Palop and Mucke, 2010 Huang and Mucke, 2012). Normal learning and memory are shaped by a balance of excitatory and inhibitory neuronal network activity ( Cui et al., 2008 Morellini et al., 2010 Andrews-Zwilling et al., 2012). More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory.
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