By Edwin J. Weeber, Ph.D.

Learn Mem. 2014 Jan 16;21(2):98-104. doi: 10.1101/lm.032375.113.

Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model.

Filonova I1, Trotter JH, Banko JL, Weeber EJ. Author information Kaphzan H1, Buffington SA, Ramaraj AB, Lingrel JB, Rasband MN, Santini E, Klann E. Author information


Angelman syndrome (AS) is associated with symptoms that include autism, intellectual disability, motor abnormalities, and epilepsy. We recently showed that AS model mice have increased expression of the alpha1 subunit of Na/K-ATPase (α1-NaKA) in the hippocampus, which was correlated with increased expression of axon initial segment (AIS) proteins. Our developmental analysis revealed that the increase in α1-NaKA expression preceded that of the AIS proteins. Therefore, we hypothesized that α1-NaKA overexpression drives AIS abnormalities and that by reducing its expression these and other phenotypes could be corrected in AS model mice. Herein, we report that the genetic normalization of α1-NaKA levels in AS model mice corrects multiple hippocampal phenotypes, including alterations in the AIS, aberrant intrinsic membrane properties, impaired synaptic plasticity, and memory deficits. These findings strongly suggest that increased expression of α1-NaKA plays an important role in a broad range of abnormalities in the hippocampus of AS model mice.


The axon initial segment (AIS) is an area of the neuron that controls whether that neuron fires or not. Synaptic activity has to be coordinated in order to depolarize the neuron to a threshold that allows the neuron to fire and give input onto another neuron. This is the basics of how signals from your visual cortex (reading this sentence) is processed and determined if it is of importance to have this become a long-lasting memory. This highly coordinated process relies on the synapse of course; however, the outcome of synaptic activity is the firing of activated neurons. This is one of the first studies to measure differences in the AS mouse model at the AIS and find increases in a protein called α1-NaKA, which is a sodium / potassium ATPase. This protein controls the excitability of the neuron. This paper not only describes a seminal finding in a potential therapeutic target outside the synapse, but also fundamentally changes how we see the global effect of Ube3a deficiency.