| First Author | Egawa K | Year | 2023 |
| Journal | Sci Rep | Volume | 13 |
| Issue | 1 | Pages | 5685 |
| PubMed ID | 37069177 | Mgi Jnum | J:335126 |
| Mgi Id | MGI:7465888 | Doi | 10.1038/s41598-023-32376-z |
| Citation | Egawa K, et al. (2023) Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model. Sci Rep 13(1):5685 |
| abstractText | 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 GABA(A) 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. |
