UCSF

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to the formation of memories. Apolipoprotein (apo) E4 and amyloid-beta (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and death and aberrant neuronal activity in the hippocampal dentate gyrus in AD-like mouse models and in humans, leading to learning and memory deficits. To determine if replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic medial ganglionic eminence (MGE)-derived interneuron progenitors into the dentate gyrus hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, largely restricted hilar transplantation of inhibitory interneurons restores normal cognitive function measured by Morris water maze, open field, and elevated plus maze 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. More broadly, it demonstrates that excitatory and inhibitory balance is 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.