Abstract: Multiple neurodegenerative and neuropsychiatric diseases, including Alzheimer's disease, schizophrenia, and epilepsy, involve the loss or dysfunction of inhibitory interneurons, particularly parvalbumin (PV)-expressing GABAergic interneurons. These are critical for maintaining neuronal network balance. Neural reprogramming represents a potential approach for interneuron restoration by converting non-neuronal cell such as a glia into interneurons with forced gene expression. The process bypasses the stem cell state – that makes it applicable in vivo with minimized risk of tumorigenesis – i.e. in vivo reprogramming. In our group, we have successfully reprogrammed human glial progenitor cells (GPCs) into PV interneurons and transplanted them into the prefrontal cortex of immunodeficient mice where they survive for up to 10 months, with mature neuronal markers and function. We have furthermore applied in vivo reprogramming of the human glia using doxycycline activated vectors. Preliminary studies demonstrate that, transplantation into the lateral ventricle—a neurogenic niche—of newborn mice provided superior survival and integration of human GPCs and enhanced their conversion to interneurons compared to the juvenile cortex. Ongoing studies investigate the long-term survival and neuronal subtype and function of these human in vivo reprogrammed neurons. Our strategy aims support the development of in vivo reprogramming strategies for interneuron-related disorders.
Funding Source: Knut and Alice Wallenberg foundation Olle Engkvist foundation Swedish research council
