WesternU Researchers Unveil New Mechanism in the Regulation of Learning and Memory

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An interprofessional team of scientists at Western University of Health Sciences has published a paper that potentially explains why children with Angelman syndrome have learning and memory impairment.

An interprofessional team of scientists at Western University of Health Sciences has published a paper that potentially explains why children with Angelman syndrome have learning and memory impairment.

The paper, “UBE3A regulates synaptic plasticity and learning and memory by controlling SK2 channel endocytosis,” by Jiandong Sun, Guoqi Zhu, Yan Liu, Steve Standley, Angela Ji, Rashmi Tunuguntla, Yubin Wang, Chad Claus, Yun Luo, Michel Baudry, and Xiaoning Bi, was published today, July 9, 2015, in Cell Reports. Click here to read the article: http://www.cell.com/cell-reports/abstract/S2211-1247(15)00621-X

Small conductance potassium channels (SKs) are critical for a variety of functions in the central nervous system, from learning and memory to rhythmic activity and sleep. This study shows that a type of SK, the synaptic SK2 channels, are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and over-expression in increased risk of autism spectrum disorder.

Angelman syndrome is a neurodevelopmental disorder largely due to abnormal maternal expression of the UBE3A gene. Characteristics include developmental delay, lack of speech, seizures, and walking and balance disorders.

“This SK2 channel is located at excitatory glutamatergic synapses, which account for more than 90 percent of the synapses in the brain and play an important role in learning and memory,” said College of Osteopathic Medicine of the Pacific Professor Xiaoning Bi, PhD, MD, principal investigator of the study. “We previously showed that learning and memory impairment, as well as synaptic plasticity impairment in the Angelman mouse model, could be rescued by enhancing excitatory synaptic transmission, in particular by increasing the function of the AMPA receptors with a drug called ampakine.”

There are two types of receptors for the excitatory neurotransmitter glutamate – AMPA and NMDA receptors. The AMPA receptor is responsible for normal depolarization. The NMDA receptor requires much more depolarization to be activated because the channel is blocked by magnesium in a voltage-dependent manner.

“You need to depolarize the membrane to get rid of this magnesium blockade. Then the channel opens, and when it opens it’s not just a sodium channel, it’s a calcium channel,” said Graduate College of Biomedical Sciences Dean Michel Baudry, PhD, who co-authored the paper. “So you get an influx of calcium from the NMDA receptor.”

The NMDA receptor is critical for synaptic plasticity and learning.

“If you block the NMDA receptor you don’t get learning,” Baudry said. “If you facilitate the function of AMPA receptors you facilitate the activation of NMDA receptors, because you are going to produce more depolarization.”

The NMDA receptor allows calcium to come in, which activates SK2 channels, resulting in hyperpolarization and inhibition of the NMDA receptors. Thus, the SK2 channels and the NMDA receptors constitute a closed feedback loop.

“This is a very fine-tuned regulation mechanism,” Bi said. “We found that the E3 ligase regulates the amount of SK2 channels at the synapse. So if you take out the E3 ligase you have too much of the SK2 channel, and it is more difficult to activate the NMDA receptors. We think that is the mechanism why in the Angelman mouse model and in patients, they cannot learn efficiently, because of this overexpression of SK2 channels.

“There are several novel findings. One is that the SK2 channel is regulated by UBE3A ligase. That was not known,” Bi said. “The second thing is in the Angelman syndrome mouse model, because the ligase is missing, there is accumulation of SK2 channels at synapses, which creates a break on the NMDA receptor, which limits how much learning can take place. If you can overcome this break, then you can rescue this learning deficit.”

This study, in combination with other work conducted by Baudry, Bi and their collaborators, provides additional pieces to the puzzle of how learning and memory works. Baudry has been studying a particular kind of protein degradation, the calcium-dependent protease calpain. Lack of a specific isoform of calpain, calpain-1, is also associated with impairment in synaptic plasticity and in learning and memory.

“Here we are talking about a different mechanism of protein degradation, which is the proteasome,” Baudry said, since the E3 ligase, by tagging proteins with ubiquitin, stimulates their degradation. “We are discovering a general principle: imbalance between protein synthesis and protein degradation is critical for a lot of disorders. In both cases, lack of calpain or lack of UBE3A, what we are finding are alterations in a set of mechanisms, which are very important to control synaptic plasticity, which in the broad sense is what allows you to learn, what allows you to adjust to changes in the environment and to resist particular insults.”


About Western University of Health Sciences

Western University of Health Sciences (http://www.westernu.edu), located in Pomona, Calif. and Lebanon, Ore., is an independent nonprofit health professions university, conferring degrees in biomedical sciences, dental medicine, health sciences, medical sciences, nursing, optometry, osteopathic medicine, pharmacy, physical therapy, physician assistant studies, podiatric medicine and veterinary medicine. WesternU is home to the Patient Care Center, where the best in collaborative health care services is offered. The Chronicle of Higher Education named WesternU a Great College to Work For in 2012, 2013 and 2014.

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