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WesternU Team Advances Understanding of Mechanisms of Learning and Neural Degeneration
Date:1/7/2014

Pomona, California (PRWEB) January 07, 2014

Two new publications by a team from Western University of Health Sciences shed further light on the mechanisms of learning and memory, and neuronal degeneration.

The first paper, “A molecular brake controls the magnitude of long-term potentiation,” by Yubin Wang, Guoqi Zhu, Victor Briz, Yu-Tien Hsu, Xiaoning Bi and Michel Baudry, was published Jan. 7, 2014 in Nature Communications. This paper shows the existence of a molecular brake that limits the amount of information that can be stored in one episode of learning. Click here to find the article at Nature Communications: http://www.nature.com/ncomms/index.html.

WesternU Graduate College of Biomedical Sciences Dean Michel Baudry, PhD, has investigated the mechanisms of learning and memory for 30 years, and this study builds upon the basic principles that he and others have developed in that time.

Brain-derived neurotrophic factor (BDNF) and its signaling pathway play an important role in the cellular mechanisms underlying long-term potentiation (LTP) of synaptic transmission elicited by a train of electrical stimulation, a molecular mechanism of certain forms of long-term memory formation. In particular, BDNF has been shown to stimulate dendritic protein synthesis, another critical step in the formation of long-lasting memories.

Calpain is a calcium-dependent protease that normally is not activated in a cell until there is an influx of calcium. Proteases are enzymes that degrade other proteins. The protease calpain is unique in that when it cleaves its targets, it produces a long-lasting modification of their functions. There are two major forms of this protease in the brain: m-calpain and mu-calpain.

Baudry’s team had previously found that the mechanism by which BDNF stimulates local protein synthesis is through BDNF-mediated stimulation of m-calpain, and that the critical target of m-calpain to mediate this effect was PTEN (phosphatase and tensin homolog deleted on chromosome ten), a known tumor suppressor protein.

“We knew that LTP requires BDNF release,” Baudry said. “BDNF activates m-calpain; m-calpain cleaves this PTEN protein, which produces stimulation of local protein synthesis. But we still had not shown that LTP directly engages m-calpain.”

This paper addresses the respective roles of mu- and m-calpain in the mechanisms underlying LTP, and therefore learning and memory.

Overexpression of suprachiasmatic nucleus circadian oscillatory protein (SCOP), a negative ERK regulator, had been shown to block long-term memory encoding.

Inhibition of calpain-mediated SCOP degradation also prevents the formation of long-term memory, suggesting that calpain-mediated SCOP breakdown is necessary for memory encoding. However, whether SCOP levels also control the magnitude of LTP was unknown.

“We report here the surprising finding that LTP induction produces rapid µ-calpain-mediated SCOP degradation, while SCOP re-synthesis during a one-hour period following LTP induction is mediated by m-calpain-induced PTEN degradation and stimulation of local protein synthesis,” according to the study.

“We propose that mu-calpain promotes long-term potentiation induction by degrading SCOP and activating a protein kinase, which has been repeatedly shown to be involved in synaptic plasticity and memory formation, the extracellular signal-regulated kinase, ERK, while m-calpain activation limits the magnitude of potentiation by terminating the ERK response via enhanced SCOP synthesis. This unique braking mechanism could account for the advantages of spaced vs. massed training in the formation of long-term memory.”

The Baudry lab had been struggling to convince the scientific community that calpain was playing a critical role in LTP, and in learning and memory.

“That’s where we got the big breakthrough. When we put this calpain inhibitor after the train to induce LTP, we found that it enhanced the magnitude of long-term potentiation,” Baudry said. “This only takes place during a short period of time after a train of high-frequency stimulation. If we give the inhibitor one hour after, it has no effect. Between 0 and 1 hour, activation of m-calpain restricts the extent of potentiation. That’s why we call it a molecular brake.

“People have known for a very long time that if you want to learn, it’s better to space the learning trials,” he added. “Repetition facilitates learning, but it’s better to space the repetition rather than cram it into a short period of time. We think that this molecular brake is responsible for this effect.”

The second paper, “Distinct Roles for mu-Calpain and m-Calpain in Synaptic NMDAR-Mediated Neuroprotection and Extrasynaptic NMDAR-Mediated Neurodegeneration,” by Yubin Wang, Victor Briz, Athar Chishti, Xiaoning Bi and Michel Baudry, published in The Journal of Neuroscience as a feature article, looks at the roles of the same two calpain isoforms, (mu- and m-) in the consequences of prolonged activation of NMDA receptors, which are glutamate receptors that are critical for learning. Click here to view the article: http://www.jneurosci.org/content/33/48/18880.

A brief activation of the NMDA receptor will provide a brief influx of calcium, which will produce long-term potentiation. But if you overactivate the receptor, you produce a massive influx of calcium, which can then lead to neural degeneration, Baudry said.

There are two types of NMDA receptors – synaptic receptors and extrasynaptic NMDA receptors, which are located on the surface of neurons but not at synaptic sites.

People have already discussed the idea that synaptic NMDA receptors are signaling pathways leading to neural protection, while extrasynaptic NMDA receptors are associated with signaling pathways leading to neural degeneration. This paper examines whether calpain activation participates in either or both of these processes, neural protection or neural degeneration.

“The surprising result is that these two isoforms of calpain are performing opposite functions, with mu-calpain being activated by the synaptic NMDA receptors and required for the neural protection effect and extrasynaptic NMDA receptors activating the m-calpain, leading to neural degeneration,” Baudry said.

“If we can selectively block m-calpain, we can prevent at least some forms of neural degeneration,” he added. “So when you combine both stories, we reach the conclusion that a selective m-calpain inhibitor would be neuroprotective and would also facilitate learning and memory. Therefore, it may be possible to develop one of these compounds as a potential therapeutic agent for quite a lot of applications, not only learning and memory impairment, but neural degeneration or a combination of both.”

The research team has filed a patent on the use of selective m-calpain inhibitors to facilitate learning, and to limit neuronal degeneration.

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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. The Chronicle of Higher Education named WesternU a Great College to Work For in 2012 and 2013.

Read the full story at http://www.prweb.com/releases/2013/12/prweb11432083.htm.


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