Generating human parvalbumin interneurons through 3D glia reprogramming

Abstract

Parvalbumin (PV) interneurons are crucial for synaptic plasticity, and their damage or loss is linked to various neurological disorders. Yet, generating these cells of human source in vitro is challenging, limiting advancements in cell repair and disease modelling. We introduce a novel approach to derive human PV neurons through direct reprogramming of glial precursor cells (GPCs). Using ectopic expression of GABAergic neuronal genes, GPCs efficiently convert into GABAergic interneurons in 3D culture environment within weeks and achieve functional neuronal maturity. Single-nuclei RNA sequencing identified a distinct PV neuronal cluster with high maturity and characteristics of PV chandelier subclass that are equivalent to bona fide human interneurons. Trajectory analysis revealed a distinct glia-to-PV interneuron conversion pathway, involving several new transitory genes, with potential for functional importance for PV derivation. Our data introduces a new strategy for generating human PV interneurons, promising significant implications for future generation of patient-specific PV neurons both in vitro and in vivo. HighlightsO_LIA novel approach to derive human PV interneurons by direct glia reprogramming. C_LIO_LIFirst comprehensive transcriptomic profiling of induced human PV interneurons. C_LIO_LIInduced PV interneurons are of chandelier subtype with transcriptional similarity to bona fide interneurons. C_LIO_LISuccessful glia-to-PV interneuron conversion passes through a specific reprogramming trajectory and involves key genes with functional potential. C_LI