Exploratory Single-Nucleus RNA Sequencing Suggests Glial-Specific NPY Upregulation and Cell-Type-Specific Metabolic...

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, but cell-type-specific molecular alterations in the epileptic cortex remain incompletely characterized. We performed single-nucleus RNA sequencing on temporal cortex from three patients with drug-resistant TLE and two non-epileptic controls, retaining 66,932 nuclei. Seven major cell types were annotated. Neuropeptide Y (NPY) was significantly upregulated in microglia and oligodendrocytes under stringent criteria (|log₂FC| > 1, adjusted p < 0.01), whereas changes in other cell types did not meet this threshold. Microglia showed enrichment of neuropeptide- and inflammatory-related pathways, together with reduced oxidative phosphorylation signatures. Oligodendrocytes showed altered lipid metabolism, together with reduced mitochondrial energy-related signatures. Inferred intercellular communication was globally reduced in the TLE samples. qPCR in an independent small set showed an upward trend of NPY expression, though not statistically significant. Given the limited cohort size, these results should be interpreted as exploratory. They provide a cell-type-resolved candidate framework for future mechanistic studies of glial-associated responses in human epilepsy.