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

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.