Disease-associated neuronal states reshape cortical architecture and inhibitory circuitry in focal cortical dysplasia type II

Focal cortical dysplasia (FCD) type II is an mTORopathy characterised by dysmorphic neurons (DNs) and balloon cells (BCs), but how these populations shape cortical architecture and epileptogenic circuits remains unclear. We combined single-nucleus RNA sequencing, multiplex spatial proteomics, and targeted patch-clamp recordings on paediatric FCDII and control cortex to build a multimodal cellular atlas. snRNA-seq revealed a conserved NEFMhigh excitatory neuronal state that was enriched in FCDII, reproducible across independent FCD datasets, and shared with other cortical mTOR-driven malformations. Spatial profiling identified NEFM as a soma-restricted marker of pS6-positive DNs and uncovered BC-rich, vimentin-positive microtuber-like domains that were specific to FCDIIb. DNs were instead dispersed throughout the lesion and embedded within inhibitory-remodelled microenvironments marked by enhanced perisomatic GAD1, intracellular KCC2 accumulation, a pacemaker-like transcriptional programme, and depolarising GABAergic activity in ex vivo recordings. These data assign BCs as principal drivers of tissue-level architectural disruption and identify DNs as intrinsic pacemaker neurons wired into altered inhibitory networks, providing a cell-type-resolved framework that links mTOR-driven mosaicism to cortical disorganisation and circuit dysfunction in human FCD II.