New research on neuronal glutamate regulation

[Bernard]

Rice University study finds possible clues to epilepsy, autism

Negative feedback gets positive results in neurological research

Rice University researchers have found a potential clue to the roots of epilepsy, autism, schizophrenia and other neurological disorders.

While studying the peripheral nerves of the Drosophila, aka the fruit fly, Rice doctoral student Eric Howlett discovered an unanticipated connection between glutamate – an amino acid and neurotransmitter in much of the food we eat – and phosphoinositide 3-kinase (PI3K), an enzyme that, Howlett found, regulates the activity of neurons.

Howlett and his colleagues, graduate student Curtis Chun-Jen Lin, research technician William Lavery and Michael Stern, a professor of biochemistry and cell biology, discovered that negative feedback mediated by PI3K regulates the excitability of neurons, an issue in a number of ailments that include neurofibromatosis, and that a mutation in a glutamate receptor gene common to both the fruit fly and humans has the ability to disrupt that regulatory mechanism.

Howlett found the Drosophila's metabotropic glutamate receptor (DmGluRA) gene, when mutated, increased the excitability of the neuron by preventing PI3K from doing its job.

Published online by the Public Library of Science Genetics, the study is the culmination of four years of work that built upon research by Marie-Laure Parmentier and her team at the University of Montpelier, France, to connect glutamate to regulatory functions in the fruit fly.

"As science often goes, we didn't set out with this hypothesis," said Howlett, who began the project on funding obtained by Stern from the Department of Defense to study neurofibromatosis. "This all came about as a control for a completely different experiment, and we said, 'Wow, this is some interesting stuff.'"

What he saw was that the overexpression of PI3K in motor neurons had a dramatic effect. "I noticed under the scope that these nerves were really big, and electrophysiologically, they were really slow. That wasn't what I expected, and it set me on a path of trying to find out what was going on."

Howlett's breakthrough was identifying the negative feedback loop that acts to maintain neuronal excitability at normal levels. "What we found was that glutamate, which is released due to neuronal activity, feeds back onto metabotropic glutamate receptors on the same neurons that released it in the first place. This leads to the activation of PI3K and ultimately to the dampening of the amount of glutamate that is released." Without that regulation, he said, things inside the cell can go terribly wrong.

"He put his heart and soul into this," said Stern of Howlett's exploration of the neuronal chain. "He was working on PI3K because that has a key role in neurofibromatosis. The Department of Defense is very interested in how PI3K is regulated in the nervous system because of its role in tumor formation."

Discovering the negative feedback loop that keeps neurons stable was key, said Stern, but not the end of the investigation. "We know that glutamate activates mGluR and PI3K, but we don't know how," he said. "There are almost certainly a number of intermediates that remain to be identified, and we have several candidates we're looking into.

"We're finding a mechanistic link among these molecules that hadn't been previously appreciated," Stern said.

"Obviously the next step would be to test whether these same molecules are playing similar roles in mammalian neurons," said Howlett, who will leave Rice in the spring to pursue postdoctoral cancer research at Virginia Commonwealth University. A native Houstonian, he earned his bachelor's in biology at the University of Houston-Clear Lake.

Howlett said mGluRs had already been targeted in possible treatments for schizophrenia, epilepsy and other "excitability" diseases, so it's not a stretch to think his research could lead to even more strategies in treating neurological ailments.

"Actually, all of the molecules involved in our model have been implicated in one way or another with neurological diseases, but no one has been able to link them together into a coherent explanation of the diseases," he said. "Our model provides a novel framework that could really go a long way toward doing that."


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The paper can be found at: http://www.plosgenetics.org/article/...l.pgen.1000277

Press Release

[RobinN]

Glutamic acid (glutamate) and aspartic acid (aspartate) are two NON-essential amino acids. Our bodies manufacture all of the required amounts of these two amino acids from other proteins. Glutamate is one of the principle neurotransmitters in our brain. The amount of glutamate at the synapse is regulated by the adjacent glial cell (astrocyte), which removes excess glutamate from the synapse to prevent over-excitation of the impulse-receiving neuron. Glutamate is not only neurostimulating, it is potentially neurologist-lethal. Excessive glutamate at the synapse is the described pathomechanism in Lou Gehrig's Disease (ALS), with that excess leading to the death of that neuron. Similarly, the "glutamate cascade" is the known cause of brain death regardless of the cause of our bodily death. Therefore, it is clearly very important for the synapse to have the proper level of glutamic acid present at any given moment. Excessive glutamate can lead to overstimulation of neurons (e.g. seizures, reduced pain threshold, sleep disorders, and emotional disturbances) or neuronal death (e.g. ALS).

9) Glutamic acid is the parent protein in MSG (mono sodium glutamate). MSG is used as a neurostimulator, acting to sensitize the open-ended nerves in our taste buds so that food will taste better. MSG is a KNOWN trigger of seizures, as is its sister amino acid, aspartic acid- the parent protein in artificial sweetener in aspartame (Nutrisweet). Both are neurostimulators (and "excitotoxins", as Dr. Russell Blaylock terms them) and the very proof lies in the purpose for their use in the food industry.

10) It has been commonly held that blood sources of these two neurostimulating amino acids do not cross the "normal" blood brain barrier, that layer of cells that protect the brain by limiting the passage of certain blood components into the brain. This contention is only partly true, as there are areas of the brain that are not protected by the normal blood brain barrier. Also, the key word in the above contention is "normal". The question is whether we have normal barriers any longer. Air pollution, hydrogenated oils, and normal immune/allergic responses are known to alter the permeability of the blood brain barrier. Therefore, with 90% of prepared foods containing trans fats, with most of us living in highly polluted environments, and with huge populations of us experiencing significant allergies, it is reasonable to question the integrity of our "normal" blood brain barrier.

11) Wheat gluten is 25% glutamic acid by weight. Casein from cow's milk is 20% glutamic acid by composition. Soy protein has much more glutamate than either of these two. Corn contains the least amount of these two non-essential amino acids but it DOES potentially do harm to the intestinal villi and IS a very common food allergen. This has become even more of a problem as we have genetically modified corn, the evidence of which came in the recent news concerning Starlink corn (CRY9C), the culprit in the "Taco Bell shell" fiasco a few years back. The reader should really search out the complete story.

12) 70% plus of the calories of the Standard American Diet (S.A.D.) come from dairy and wheat alone, the number one and number two food allergens in humans, dogs, and cats. Remember: The damage they do to the gut is the root cause of the allergies. These foods are loaded with glutamate. Allergic reactions affect the blood brain barrier. The products made from these foods are often very high in refined sugar and hydrogenated oils.

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(Bold type added by me)

[Molly97]

And again, I say Thank you dogtor j for opening my eyes to the problems of glutamate. Before I came to this website, I had no idea. As I told a doc just this morning, being glutamate, casein, corn, aspartate, soy free has made a significant difference in the frequency of my seizures and the overall quality of my life. Is it easy? Absolutely not! Is it worth it? Many, many times over.

[Zoe]

Bernard,
This is an important find. Once more we are seeing the role of diet, not drugs, in maintaining good health, or restoring it.

[IslandLiz]

Hi -- You've all been mostly dealing with changing glutamate reception via diet, but I just wanted to let you know that I've been in a Mayo-clinic sponsored anti-epileptic drug study for over a year now, trying out a new glutamate receptor antagonist. We've come out of the double-blind part of the study -- and I've been on the active drug, which was no surprise, because my complex-partial seizures of over 40 years have drastically reduced. I have hardly any whole seizures anymore, and the auras are much lighter and less full of anxiety. There will be several years more until FDA approval, but I'll bet it's approved, and then more of us can benefit from this research!

By the way, until menopause, my seizures were catamenial, and they've pretty much been mostly nocturnal for decades. This seems to fit with some of the research you all have been posting in this thread.

[Endless]

Wheat gluten is 25% glutamic acid by weight. Casein from cow's milk is 20% glutamic acid by composition. Soy protein has much more glutamate than either of these two. Corn contains the least amount of these two non-essential amino acids but it DOES potentially do harm to the intestinal villi and IS a very common food allergen.

Hey, folks. The only way you can tell for sure if this is something that affects you is to do an elimination diet. I went without soy, corn, and wheat for one month, then introduced each one back one at a time. (Dairy is never in my diet, period) It didn't make a difference for me - no effect caused by wheat or soy. Though I know it does for some. When my aunt put wheat back in her diet it made her incredibly tired, like she had mono.

When you try your elimination diet be careful and read every label. The numerous wheat products are sneaky. Especially the notorious "natural flavorings." When it's even listed in general, give it a miss. An even better way to avoid all that is to avoid packaged foods. Grow it, harvest it, cook it, eat it.

I wish the answer to my seizures was so easy - because diet is fixable.