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Updated: Sep 29, 2026
Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy
Published on: October 19, 2021
Downregulation of Ubiquitin-Specific Protease 15 (USP15) Does Not Provide Therapeutic Benefit in Experimental Mesial
Ute Häussler1,2, João Neres3, Catherine Vandenplas3
1Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany. ute.haeussler@uniklinik-freiburg.de.
Abstract:
Structural epilepsies display complex immune activation signatures. However, it is unclear which neuroinflammatory pathways drive pathobiology. Transcriptome studies of brain resections from mesial temporal lobe epilepsy (mTLE) patients revealed a dysregulation of transforming growth factor β, interferon α/β, and nuclear factor erythroid 2-related factor 2 pathways. Since these pathways are regulated by ubiquitin-specific proteases (USP), in particular USP15, we hypothesized that USP15 blockade may provide therapeutic relief in treatment-resistant epilepsies. For validation, transgenic mice which either constitutively or inducibly lack Usp15 gene expression underwent intrahippocampal kainate injections to induce mTLE. We show that the severity of status epilepticus is unaltered in mice constitutively lacking Usp15 compared to wild types. Cell death, reactive gliosis, and changes in the inflammatory transcriptome were pronounced at 4 days after kainate injection. However, these brain inflammation signatures did not differ between genotypes. Likewise, induced deletion of Usp15 in chronic epilepsy did not affect seizure generation, cell death, gliosis, or the transcriptome. Concordantly, siRNA-mediated knockdown of Usp15 in a microglial cell line did not impact inflammatory responses in the form of cytokine release. Our data show that a lack of USP15 is insufficient to modulate the expression of relevant neuroinflammatory pathways in an mTLE mouse model and do not support targeting USP15 as a therapeutic approach for pharmacoresistant epilepsy.
Insights
Targeting USP15 is ineffective for treating pharmacoresistant epilepsy. Studies show that lacking USP15 does not alter neuroinflammation or seizure generation in epilepsy models, failing to support USP15 as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Structural epilepsies exhibit complex immune activation, but specific neuroinflammatory drivers remain unclear.
- Mesial temporal lobe epilepsy (mTLE) transcriptomes show dysregulated TGF-β, IFN-α/β, and Nrf2 pathways.
- Ubiquitin-specific protease 15 (USP15) regulates these pathways, suggesting it as a potential therapeutic target.
Purpose of the Study:
- To investigate the therapeutic potential of blocking USP15 in treatment-resistant epilepsy.
- To determine if USP15 deficiency impacts neuroinflammation and seizure activity in an mTLE mouse model.
Main Methods:
- Generated transgenic mice lacking Usp15 constitutively or inducibly.
- Induced mTLE using intrahippocampal kainate injections.
- Assessed seizure severity, cell death, reactive gliosis, and inflammatory transcriptome.
- Utilized siRNA-mediated knockdown of Usp15 in microglial cell lines.
Main Results:
- Constitutive Usp15 deficiency did not alter status epilepticus severity compared to wild types.
- Brain inflammation signatures, cell death, and gliosis were similar between Usp15-deficient and wild-type mice post-kainate.
- Induced Usp15 deletion in chronic epilepsy did not affect seizure generation or neuropathology.
- Usp15 knockdown in microglia did not alter inflammatory cytokine release.
Conclusions:
- USP15 deficiency does not modulate key neuroinflammatory pathways in an mTLE mouse model.
- Targeting USP15 is insufficient to impact epilepsy pathobiology.
- USP15 is not a viable therapeutic target for pharmacoresistant epilepsy.
