Aberrant medial ganglionic eminence (MGE) GABAergic neurogenesis contributes to Huntington's disease pathogenesis.

Abstract

Although early telencephalic interneuron dysfunction in animal models and cortical interneuron deficits in Huntington's disease (HD) have been documented, their developmental origins and causal contributions to disease pathogenesis remain incompletely understood. Using the BACHD mouse model, we examined medial ganglionic eminence (MGE)-derived GABAergic lineage development across embryonic and early postnatal stages, integrated single-cell transcriptomic analyses of E12.5 MGE progenitors and assessed disease relevance through lineage-specific genetic rescue. At postnatal day (PND) 13, BACHD mice exhibited reduced numbers of cortical somatostatin-positive (SST) and parvalbumin-positive (PV) interneurons, as well as striatal PVinterneurons, accompanied by a selective expansion of a Foxp2arkypallidal neuron subpopulation in the globus pallidus. By PND30, PVinterneuron deficits were no longer detected, whereas cortical SSTinterneuron reductions persisted. Single-cell RNA sequencing revealed that mutant huntingtin disrupts early MGE neurogenic programs, with basal intermediate progenitors representing a primary site of cell vulnerability. These cells displayed coordinated repression of replication-dependent histone genes, reduced expression of the chromatin regulator Erh, mitochondrial and ribosomal deficits, and altered cell-cycle dynamics characterized by S-phase accumulation without increased mitotic output. Consistent with these findings, immunohistochemical analyses revealed reduced interneuron precursors within E12.5 subpallial migratory corridors and increased Nkx2-1/Dlx1precursors in developing globus pallidus regions. Importantly, conditional excision of mutant Htt within Nkx2-1-derived MGE lineages rescued early interneuron deficits, HD-like motor impairments and striatal degeneration. Together, these findings identify disrupted MGE neurogenesis as a key developmental mechanism contributing to HD pathogenesis and highlight associated vulnerabilities as potential early-stage disease-modifying targets.