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Updated: Jun 20, 2025
Assessment of Memory Function in Pilocarpine-induced Epileptic Mice
Published on: June 4, 2020
Temporal changes in mouse hippocampus transcriptome after pilocarpine-induced seizures
Evgenya Y Popova1,2, Yuka Imamura Kawasawa3,4, Ming Leung4
1Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, United States.
Introduction:
Status epilepticus (SE) is a seizure lasting more than 5 min that can have lethal consequences or lead to various neurological disorders, including epilepsy. Using a pilocarpine-induced SE model in mice we investigated temporal changes in the hippocampal transcriptome.
Methods:
We performed mRNA-seq and microRNA-seq analyses at various times after drug treatment.
Results:
At 1 h after the start of seizures, hippocampal cells upregulated transcription of immediate early genes and genes involved in the IGF-1, ERK/MAPK and RNA-PolII/transcription pathways. At 8 h, we observed changes in the expression of genes associated with oxidative stress, overall transcription downregulation, particularly for genes related to mitochondrial structure and function, initiation of a stress response through regulation of ribosome and translation/EIF2 signaling, and upregulation of an inflammatory response. During the middle of the latent period, 36 h, we identified upregulation of membrane components, cholesterol synthesis enzymes, channels, and extracellular matrix (ECM), as well as an increased inflammatory response. At the end of the latent period, 120 h, most changes in expression were in genes involved in ion transport, membrane channels, and synapses. Notably, we also elucidated the involvement of novel pathways, such as cholesterol biosynthesis pathways, iron/BMP/ferroptosis pathways, and circadian rhythms signaling in SE and epileptogenesis.
Discussion:
These temporal changes in metabolic reactions indicate an immediate response to injury followed by recovery and regeneration. CREB was identified as the main upstream regulator. Overall, our data provide new insights into molecular functions and cellular processes involved at different stages of seizures and offer potential avenues for effective therapeutic strategies.
Insights
Status epilepticus (SE) involves prolonged seizures and can lead to epilepsy. This study tracked hippocampal gene expression changes over time after induced seizures, revealing distinct molecular responses and potential therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Genomics
Background:
- Status epilepticus (SE) is a neurological emergency with severe consequences, including epilepsy.
- Understanding the molecular mechanisms underlying SE and epileptogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the temporal changes in the hippocampal transcriptome following pilocarpine-induced status epilepticus in a mouse model.
- To identify key molecular pathways and potential therapeutic targets involved in the acute and latent phases of SE.
Main Methods:
- Mice were subjected to pilocarpine-induced status epilepticus.
- Hippocampal mRNA and microRNA sequencing (mRNA-seq and microRNA-seq) were performed at multiple time points (1, 8, 36, and 120 hours) post-treatment.
Main Results:
- Early changes (1h) included upregulation of immediate early genes and pathways like IGF-1 and ERK/MAPK.
- Later stages (8h, 36h, 120h) showed shifts towards oxidative stress, inflammation, cholesterol biosynthesis, ion transport, and synaptic function.
- Novel pathways, including ferroptosis and circadian rhythms, were implicated in SE and epileptogenesis.
Conclusions:
- Temporal transcriptomic alterations reflect an immediate injury response followed by recovery and regeneration.
- CREB was identified as a key upstream regulator.
- The findings provide insights into SE's molecular landscape and suggest potential therapeutic strategies targeting specific pathways.
