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Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis.

Elena Cid, Angel Marquez-Galera, Manuel Valero, Beatriz Gal, Daniel C Medeiros, Carmen M Navarron, Luis Ballesteros-Esteban, Rita Reig-Viader, Aixa V Morales, Ivan Fernandez-Lamo, Daniel Gomez-Dominguez, Masaaki Sato, Yasunori Hayashi, Àlex Bayés, Angel Barco, Jose P Lopez-Atalaya, Liset M de la Prida.

Cell Rep. 2021 Jun 8;35(10):109229
PMID: 34107264 DOI: doi: 10.1016/j.celrep.2021.109229

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Video "Descifrada las claves genómicas de la atrofia del hipocampo y la muerte neuronal en la epilepsia" »

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation 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.

Angel Márquez-Galera, Jose P. López-Atalaya

Elena Cid, Liset M.de la Prida

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