Journal
CELL REPORTS
Volume 35, Issue 10, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109229
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Funding
- MICINN [BES-2013-064171, BES2016-076281, SAF201785717-R, RTI2018-098581-B-I00, SAF2017-87928-R]
- Fundacion Tatiana Perez de Guzman el Bueno
- SynCogDis Network [SAF2014-52624-REDT, SAF201790664-REDT]
- MICIU
- ERDF [RYC-2015-18056, RTI2018-102260-B-I00]
- Severo Ochoa grant [SEV-2017-0723]
- MINECO [BFU2015-69717-P, RTI2018-097037-B-100]
- Marie Curie career integration grant [304111]
- Fundacion Alicia Koplowitz
- Human Frontiers Science Program Organization [RGP0039/2017]
- ERDF
- Human Frontiers Science Program (HFSP) [RGP0022/2013]
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Hippocampal sclerosis, a major neuropathological feature of temporal lobe epilepsy, is characterized by overactive superficial CA1 pyramidal neurons in epileptic rodents. Single-cell gene expression analysis reveals sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Neurodegenerative signatures primarily involve superficial cells.
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.
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