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 (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.