Chronic α1-Na/K-ATPase inhibition reverses the elongation of the axon initial segment of the hippocampal CA1 pyramidal neurons in Angelman syndrome model mice

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene. The hippocampus is one of the most prominently affected brain regions in AS model mice, manifesting in severe hippocampal-dependent memory and plasticity deficits. Previous studies in AS mice reported an elongated axon initial segment (AIS) in pyramidal neurons (PNs) of the hippocampal CA1 region. These were the first reports in mammals to show AIS elongation in vivo. Correspondingly, this AIS elongation was linked to enhanced expression of the α1 subunit of Na+/K+-ATPase (α1-NaKA). Recently, it was shown that selective pharmacological inhibition of α1-NaKA by marinobufagenin (MBG) in adult AS mice rescued the hippocampal-dependent deficits via normalizing their compromised activity-dependent calcium (Ca+2) dynamics. In the herein study, we showed that a chronic selective α1-NaKA inhibition reversed the AIS elongation in hippocampal CA1 PNs of adult AS mice, and differentially altered their excitability and intrinsic properties. Taken together, our study is the first to demonstrate in vivo structural plasticity of the AIS in a mammalian model, and further elaborates on the modulatory effects of elevated α1-NaKA levels in the hippocampus of AS mice.

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Fig. 1: Chronic selective α1-NaKA inhibition shortens the elongated AIS of CA1 PNs in AS mice to the WT length.
Fig. 2: Chronic selective α1-NaKA inhibition does not affect AIS length in layer-5 PNs at SSCtx of AS mice.
Fig. 3: Chronic selective α1-NaKA inhibition partially rescues excitability alterations in CA1 PNs of AS model mice.
Fig. 4: Chronic selective α1-NaKA inhibition differentially rescues the membrane properties of CA1 PNs in AS model mice.

Data availability

All data presented in this study can be obtained from the corresponding author upon request.

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PRR performed all the experiments. PRR and HK designed and analyzed the AIS experiments; PRR and HK designed and analyzed the electrophysiology experiments; HK conceptualized all the experiments; AYB extracted the marinobufagenin; PRR and HK wrote the manuscript.

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Correspondence to Hanoch Kaphzan.

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Rayi, P.R., Bagrov, A.Y. & Kaphzan, H. Chronic α1-Na/K-ATPase inhibition reverses the elongation of the axon initial segment of the hippocampal CA1 pyramidal neurons in Angelman syndrome model mice. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00907-1

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