Human iPSC-derived GABAergic interneuron transplantation restores circuit balance and cognitive function in an
Xinzhe Zhang1,2, Gaojie Wang1, Haodong Chen1
1Department of Neurology, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Science(CAMS), Beijing, China.
Introduction:
Alzheimer's disease (AD) is characterized by disrupted excitatory-inhibitory (E:I) balance and impaired synaptic function, yet current treatments fail to repair these fundamental circuit impairments.
Methods:
Human induced pluripotent stem cell-derived post-mitotic medial ganglionic eminence-originated inhibitory neurons (MGE-pINs) were bilaterally transplanted into the hippocampus of 10-month-old 5xFAD mice. Cell transplantation effects were assessed by behavioral analysis, electrophysiology, immunofluorescence staining, immunoblotting, and RNA sequencing analysis.
Results:
MGE-pIN integration restored local inhibition, correcting E:I imbalance and suppressing electroencephalogram (EEG)-detected epileptiform discharges. This network recovery, underpinned by normalized receptor subunit levels and restored synaptic plasticity - as evidenced by long-term potentiation recordings, morphological analysis, and transcriptomic profiling - led to the rescue of cognitive deficits. Importantly, these functional benefits occurred independently of amyloid beta levels.
Discussion:
The study's findings suggest that targeted interneuron replacement can reverse network dysregulation and cognitive decline in AD, underscoring the potential of cell-based modulation as a route to restore brain function in neurodegenerative disorders.
