The Latest Research for Angelman Syndrome
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 
Abstract
Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal UBE3A gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular mechanisms whereby Ube3a deficiency results in AS are enigmatic. Using in vitro and in vivo systems we show dramatic changes in the expression of Ube3a following synaptic activation. In primary neuronal culture, neuronal depolarization was found to increase both nuclear and cytoplasmic Ube3a levels. Analogous up-regulation in maternal and paternal Ube3a expression was observed in Ube3a-YFP reporter mice following fear conditioning. Absence of Ube3a led to deficits in the activity-dependent increases in ERK1/2 phosphorylation, which may contribute to reported deficits in synaptic plasticity and cognitive function in AS mice. Taken together, our findings provide novel insight into the regulation of Ube3a by synaptic activity and its potential role in kinase regulation.
Synopsis:
Nearly all research looking into the molecular changes in the brains of the Angelman syndrome mouse model examine the brain in a static condition. Brain chemistry is incredible difficult to research and in order to measure differences in the AS model versus non-AS model it is often studied in brains removed from aestheticized animals and quickly put in cold solutions to stop any biochemical activity. In this study, memory formation was induced and then biochemical changes were determined. They find that Ube3a protein is not stable, but changes in the brain following neuronal activation from both maternal and paternal genes! Also, a main enzyme called extracellular regulated kinase (ERK), know for years to be highly involved in memory formation, shows reduced activity following memory training. These studies show that there may be significant changes in the AS mouse brain that have yet to be identified under neuronal activity conditions, including changes in Ube3a gene expression.
Cell Rep. 2013 Aug 15;4(3):405-12. doi: 10.1016/j.celrep.2013.07.005. Epub 2013 Aug 1.
Genetic reduction of the α1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome.
Kaphzan H1, Buffington SA, Ramaraj AB, Lingrel JB, Rasband MN, Santini E, Klann E. Author information
Abstract:
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.
Synopsis:
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.