RE: Glutamate: Clues Tot Of Epilepsy, Autism, Schizophrenia: phosphoinositide 3-kinase (PI3K)

[Guest guest]

OUTSTANDING ARTICLE ON GLUTAMATES.

Apprecited.

Lidia

_____

From: csb-autism-rx [mailto:csb-autism-rx ]

On Behalf Of binstock

Sent: Thursday, December 18, 2008 12:15 PM

To: abmd ; autisminfo ;

AutismRecoveryWA ; csb-autism-rx

Subject: Glutamate: Clues To Root Of Epilepsy, Autism,

Schizophrenia: phosphoinositide 3-kinase (PI3K)

Study is free online, link hereinbelow

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Possible Clues To Root Of Epilepsy, Autism, Schizophrenia

ScienceDaily (Dec. 17, 2008) --- 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 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 Lavery and 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.

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. "

Journal reference:

1. Howlett et al. *A PI3-Kinase--Mediated Negative Feedback Regulates

Neuronal Excitability*. /PLoS Genetics/, 2008; 4 (11): e1000277

DOI: 10.1371/journal.pgen.1000277

<http://dx.doi. <http://dx.doi.org/10.1371/journal.pgen.1000277>

org/10.1371/journal.pgen.1000277>

..