Epilepsy is one of the most common neurological disorders, yet its pathophysiology
is poorly understood due to the high complexity of affected neuronal circuits. To
identify dysfunctional neuronal subtypes underlying seizure activity in the human
brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal
transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy
and non-epileptic subjects. We found that the largest transcriptomic changes occur
in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2
and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes
in the same families were less affected. Furthermore, the subtypes with the largest
epilepsy-related transcriptomic changes may belong to the same circuit, since we observed
coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited
one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional
changes in multiple glutamate receptor genes and strong upregulation of genes coding
for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific
molecular phenotype of epilepsy.
