A self-healing brain for neurological disorders - turning glia cells into interneurons

Neurological disorders such as schizophrenia and epilepsy are linked to damage of inhibitory parvalbumin (PV) interneurons.

There are indication that interneuron restoration could counteract disease pathology but PV interneurons are difficult to derive in vitro.

In vivo direct reprogramming is an attractive alternative strategy to generate human neurons from resident cells directly in the brain by forced expression of transcription factors, providing a safe and fast way to neural restoration.

With this technique, my team has been first to demonstrate generation of PV interneurons in the living mouse brain and further converted human glia cells into PV interneurons in vitro.This project will generate human PV interneurons using in vivo reprogramming in a 3D culture system of human glia.

Converted neurons will be assessed with Patch-seq and compared to endogenous interneurons to unravel critical molecular determinants for a genuine PV fate that can improve the reprogramming further.

These will then be applied on human glia placed in mouse in vivo model or ex vivo human-organotypic culture model that enable reconnection to neuronal circuitry.

At last, human interneurons will be evaluated for restoration of disease phenotype and brain circuitry in a mouse schizophrenia model.This will be unique in using human cells for in vivo reprogramming that constitutes the critical step towards a restorative therapy for interneuron disorders where the brain can heal itself.