Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model
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Kiyoshi Egawa1, Miho Watanabe2, Hideaki Shiraishi3
1Department of Pediatrics, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, 060-8638, Japan. egakiyo@huhp.hokudai.ac.jp.
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.
Insights
Angelman syndrome involves altered cation-chloride cotransporter expression, impacting neuronal function. Inhibiting NKCC1 with bumetanide improved cognitive deficits and reduced seizures in mouse models, suggesting a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Angelman syndrome is a neurodevelopmental disorder stemming from the loss of the UBE3A gene.
- Current treatments for Angelman syndrome manifestations like cognitive dysfunction and epilepsy are limited.
- Cation-chloride cotransporters (CCCs), specifically NKCC1 and KCC2, are implicated in neurological disorders due to their role in regulating intracellular chloride concentration ([Cl-]i).
Purpose of the Study:
- To investigate the role of CCCs in Angelman syndrome pathophysiology.
- To evaluate the therapeutic potential of NKCC1 inhibition using bumetanide in Angelman syndrome mouse models.
Main Methods:
- Analysis of NKCC1 and KCC2 expression in the hippocampi of Ube3am-/p+ mice (Angelman syndrome model).
- Measurement of intracellular chloride concentration ([Cl-]i) in CA1 pyramidal neurons.
- Assessment of tonic GABAA receptor-mediated chloride conductance.
- Evaluation of the effects of bumetanide on cognitive function and seizure susceptibility in Ube3am-/p+ mice.
Main Results:
- Ube3am-/p+ mice exhibited increased NKCC1 and decreased KCC2 expression.
- While average [Cl-]i was unchanged, its variance increased in Ube3am-/p+ mice, potentially due to reduced tonic GABAA receptor-mediated chloride conductance.
- Bumetanide treatment restored cognitive function and reduced seizure susceptibility in Ube3am-/p+ mice.
Conclusions:
- Imbalanced CCC expression contributes to Angelman syndrome pathophysiology, even without altered average intracellular chloride levels.
- NKCC1 inhibition with bumetanide shows promise as a therapeutic strategy for Angelman syndrome.
- Targeting CCCs represents a potential avenue for treating cognitive dysfunction and epilepsy in Angelman syndrome.
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