Acta neuropathologica communications · 2026
A stage-resolved neuron-glia transcriptional atlas reveals a glial inflammatory pivot in epilepsy.
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Berger Toni Christoph, Vigeland Magnus Dehli, Hjorthaug Hanne Sagsveen, Nome Cecilie Gjessing, Beier Christoph Patrick, Taubøll Erik, Selmer Kaja Kristine, Heuser Kjell
Аннотация
BACKGROUND: Epileptogenesis transforms a healthy brain into an epileptic network, yet the temporal and cell-type-specific molecular events driving this transition remain poorly defined. Neuron-glia interactions are essential in this process, but no study has systematically charted their transcriptional dynamics from the acute insult to chronic epilepsy.
METHODS: Using the intracortical kainic acid mouse model that recapitulates key hallmarks of mesial temporal lobe epilepsy with hippocampal sclerosis in humans, we performed Fluorescent Activated Nuclear Sorting of NeuN+ (neuronal) and NeuN⁻ (glia) nuclei followed by RNA sequencing at 1 h, 24 h, and 3 months after status epilepticus. Differential expression and integrative GO/KEGG analyses resolved stage-specific molecular programs across cell types.
RESULTS: The majority of genes differentially expressed in neurons and glia were exclusive to the respective time point investigated. We also identify a sequential reorganization of cellular gene expression changes during epileptogenesis. The acute phase is dominated by a shared stress response and DNA-repair programs in both neurons and glia. At 24 h, glia undergoes a marked transcriptional pivot involving necroptosis-associated, TNFR1/IFN-linked, and COX-2/chemokine pathways, while neurons display immune- and plasticity-related signatures. By 3 months, transcriptional activity is largely confined to glia and enriched for inflammatory, angiogenic, and gliogenic processes, consistent with long-term neurovascular remodeling. Only a few transcripts, including Parp3 (neurons) and Tlr1 (glia), are dysregulated across all stages.
CONCLUSION: These findings reveal an orderly transition from an acute protective-leaning program to a early latent glial inflammatory/regulated-death state, culminating in chronic gliopathy. Our work provides, to our knowledge, the first cell-type-resolved temporal atlas of epileptogenesis and identifies the early latent phase as a mechanistically tractable window for antiepileptogenic intervention.
METHODS: Using the intracortical kainic acid mouse model that recapitulates key hallmarks of mesial temporal lobe epilepsy with hippocampal sclerosis in humans, we performed Fluorescent Activated Nuclear Sorting of NeuN+ (neuronal) and NeuN⁻ (glia) nuclei followed by RNA sequencing at 1 h, 24 h, and 3 months after status epilepticus. Differential expression and integrative GO/KEGG analyses resolved stage-specific molecular programs across cell types.
RESULTS: The majority of genes differentially expressed in neurons and glia were exclusive to the respective time point investigated. We also identify a sequential reorganization of cellular gene expression changes during epileptogenesis. The acute phase is dominated by a shared stress response and DNA-repair programs in both neurons and glia. At 24 h, glia undergoes a marked transcriptional pivot involving necroptosis-associated, TNFR1/IFN-linked, and COX-2/chemokine pathways, while neurons display immune- and plasticity-related signatures. By 3 months, transcriptional activity is largely confined to glia and enriched for inflammatory, angiogenic, and gliogenic processes, consistent with long-term neurovascular remodeling. Only a few transcripts, including Parp3 (neurons) and Tlr1 (glia), are dysregulated across all stages.
CONCLUSION: These findings reveal an orderly transition from an acute protective-leaning program to a early latent glial inflammatory/regulated-death state, culminating in chronic gliopathy. Our work provides, to our knowledge, the first cell-type-resolved temporal atlas of epileptogenesis and identifies the early latent phase as a mechanistically tractable window for antiepileptogenic intervention.