Temporal lobe epilepsy is associated with hippocampal sclerosis, which is characterized by specific patterns of neuronal loss along hippocampal subfields from the CA1 to CA3/4 areas. Mechanisms underlying such a cell-type specificity remain unknown. We discovered that a subtype ot pyramidal neurons (superficial CA1 cells) are overactive in epileptic rodents (Cid, Marquez-Galera et al., Cell reports 2021). Pseudotemporal analysis of single-cell transcriptional responses reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis.