Transplantation of GABAergic Interneuron Progenitors Restores Cortical Circuit Function in an Alzheimer's Disease Mouse Model

Abstract In addition to dementia, Alzheimer's patients suffer from sleep impairments and aberrations in sleep‐dependent brain rhythms. Deficits in inhibitory GABAergic interneuron function disrupt one of those rhythms, slow oscillation in particular, and actively contribute to Alzheimer's progression. The degree to which transplantation of healthy donor interneuron progenitors restores slow oscillation rhythm in young APP/PS1 mice is tested. Medial ganglionic eminence (MGE) progenitors are harvested from mouse embryos and transplanted them into host APP/PS1 mutant cortices. 3D light‐sheet and structured illumination microscopy revealed that transplanted MGE progenitors survived and matured into healthy interneurons. In vivo multiphoton calcium imaging and voltage‐sensitive dye imaging showed functional integration and slow oscillation rescue in the absence or presence of optogenetic stimulation. The work provides proof‐of‐concept evidence that stem cell therapy may serve as a viable strategy to rescue functional impairments in cortical circuits of APP/PS1 mice and potentially those of Alzheimer's patients.