Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.

Autor: Wang Z; Multidisciplinary Brain Protection Program, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA., Li Q; Department of Neurology, Duke University Medical Center, Durham, NC, USA., Kolls BJ; Department of Neurology, Duke University Medical Center, Durham, NC, USA., Mace B; Department of Neurology, Duke University Medical Center, Durham, NC, USA., Yu S; Multidisciplinary Brain Protection Program, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA., Li X; Multidisciplinary Brain Protection Program, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA., Liu W; Department of Bioengineering, Duke University, Durham, NC, USA., Chaparro E; Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA., Shen Y; Multidisciplinary Brain Protection Program, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA., Dang L; Multidisciplinary Brain Protection Program, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA., Del Águila Á; Multidisciplinary Brain Protection Program, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA., Bernstock JD; National Institute of Neurological Disorders and Stroke, NINDS/NIH, Bethesda, MD, USA., Johnson KR; National Institute of Neurological Disorders and Stroke, NINDS/NIH, Bethesda, MD, USA., Yao J; Department of Bioengineering, Duke University, Durham, NC, USA., Wetsel WC; Department of Neurology, Duke University Medical Center, Durham, NC, USA.; Departments of Neurobiology and Cell Biology, Duke University Medical Center, Durham, NC, USA., Moore SD; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA., Turner DA; Departments of Neurosurgery, Neurobiology and Biomedical Engineering, Duke University Medical Center, Durham, NC, USA., Yang W; Multidisciplinary Brain Protection Program, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. wei.yang@duke.edu.; Department of Neurology, Duke University Medical Center, Durham, NC, USA. wei.yang@duke.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Mar 09; Vol. 6 (1), pp. 252. Date of Electronic Publication: 2023 Mar 09.
DOI: 10.1038/s42003-023-04594-8
Abstrakt: The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box-binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulated) in the brain, including several GABA A receptor genes that are notably downregulated. Finally, whole-cell patch clamp analysis reveals a significant reduction in both spontaneous and tonic GABAergic inhibitory responses in Xbp1s-expressing neurons. Taken together, our findings unravel a link between XBP1s signaling and seizure occurrence.
(© 2023. The Author(s).)
Databáze: MEDLINE
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