Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model.

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 (Ube3am-/p+ mice). We observed increased NKCC1 expression and decreased KCC2 expression in the hippocampi of Ube3am-/p+ mice. The average [Cl-]i of CA1 pyramidal neurons was not significantly different but demonstrated greater variance in Ube3am-/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 Ube3am-/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 Ube3am-/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.

• Authors: Kiyoshi Egawa, Miho Watanabe, Hideaki Shiraishi, Daisuke Sato, Yukitoshi Takahashi, Saori Nishio, Atsuo Fukuda
• Journal: Scientific reports (Sci Rep) Vol. 13 Issue 1 Pg. 5685 (04 17 2023) ISSN: 2045-2322 [Electronic] England
• PMID: 37069177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Sodium-Potassium-Chloride Symporters
• Bumetanide
• Chlorides
• Symporters
• Receptors, GABA-A

Topics

• Mice
• Animals
• Sodium-Potassium-Chloride Symporters (genetics, metabolism)
• Bumetanide (pharmacology)
• Angelman Syndrome (drug therapy, genetics)
• Chlorides (metabolism)
• Symporters (genetics, metabolism)
• Epilepsy (drug therapy, genetics)
• Receptors, GABA-A