| Autor: |
Kiyoshi Egawa, Miho Watanabe, Hideaki Shiraishi, Daisuke Sato, Yukitoshi Takahashi, Saori Nishio, Atsuo Fukuda |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Scientific Reports, Vol 13, Iss 1, Pp 1-12 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2045-2322 |
| DOI: |
10.1038/s41598-023-32376-z |
| Popis: |
Abstract Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Treatments for the main manifestations, including cognitive dysfunction or epilepsy, are still under development. Recently, the Cl− importer Na+-K+-Cl− cotransporter 1 (NKCC1) and the Cl− exporter K+-Cl− cotransporter 2 (KCC2) have garnered attention as therapeutic targets for many neurological disorders. Dysregulation of neuronal intracellular Cl− concentration ([Cl−]i) is generally regarded as one of the mechanisms underlying neuronal dysfunction caused by imbalanced expression of these cation-chloride cotransporters (CCCs). Here, we analyzed the regulation of [Cl−]i and the effects of bumetanide, an NKCC1 inhibitor, in Angelman syndrome models (Ube3a m−/p+ mice). We observed increased NKCC1 expression and decreased KCC2 expression in the hippocampi of Ube3a m−/p+ mice. The average [Cl−]i of CA1 pyramidal neurons was not significantly different but demonstrated greater variance in Ube3a m−/p+ mice. Tonic GABAA receptor-mediated Cl− conductance was reduced, which may have contributed to maintaining the normal average [Cl−]i. Bumetanide administration restores cognitive dysfunction in Ube3a m−/p+ mice. Seizure susceptibility was also reduced regardless of the genotype. These results suggest that an imbalanced expression of CCCs is involved in the pathophysiological mechanism of Ube3a m−/p+ mice, although the average [Cl−]i is not altered. The blockage of NKCC1 may be a potential therapeutic strategy for patients with Angelman syndrome. |
| Databáze: |
Directory of Open Access Journals |
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