Potential target identified for migraine therapy

Date:
September 17, 2020
Source:
Tokyo Medical and Dental University
Summary:
Researchers have identified the protein GLT-1 as the
neurotransmitter glutamate transporter in the brain that is related
to cortical spreading depression, a pathological condition that
underlies migraines. The researchers found that mice lacking GLT-1,
but not other glutamate receptors, were more susceptible to cortical
spreading depression than were controls. GLT-1 might therefore be
a potential target for migraine therapy.



FULL STORY ========================================================================== Migraines affect millions of people worldwide, often lasting days and
severely disrupting lives. More than simply super-intense headaches, some migraines actually result from pathological excitation of neurons in the
brain. A new study in mice led by Kohichi Tanaka at Tokyo Medical and
Dental University (TMDU) shows that susceptibility to migraines could
be related to a molecular transporter that normally works to prevent
excessive excitation of neurons.


========================================================================== Neurons in the brain communicate with each other by passing along
molecules called neurotransmitters. After a neurotransmitter takes care
of business, it is transported away from the synapse -- the space between
two neurons -- so that it cannot be used over and over again. This process
is called reuptake, and is one of many ways in which over-excitation of
neurons in the brain is prevented. Migraines are related to a condition
called cortical depression, in which a large wave of hyperactivity
spreads across the brain, followed by a wave of inhibition, or depressed
brain activity. Tanaka and his team hypothesized that susceptibility
to cortical spreading depression is related to disrupted transport of glutamate, the most common excitatory neurotransmitter.

In turns out that mammals have four molecules that transport glutamate,
and three of them are in the cerebral cortex. To determine which of these,
if any, is related to cortical spreading depression, the researchers
created three strains of knockout mice, each of which lacked one of the
three cortical glutamate-transporter genes. They found that when mice
lacked the GLT- 1 transporter, cortical spreading depression occurred
more frequently and spread more quickly than in control mice or in the
other knockout mice.

"We know that 90% of glutamate is transported by GLT-1 back into
astrocytes, not neurons," says Tanaka. "Our findings thus highlight
another important function of glial cells in the brain as they support
neuronal function." To confirm their findings, the team then measured the amount of glutamate outside of cells using a platinum-iridium electrode
coated with glutamate oxidase. When glutamate oxidase interacts with
glutamate, it creates a negative current that can be detected by the
electrode very quickly, allowing almost real-time measurements of
glutamate concentration in the region.

"A fast biosensor is critical," explains Tanaka, "because cortical
spreading depression only lasts about 5 minutes, and the changes in
glutamate concentration could never be found using conventional methods
that take minutes to hours of sampling." When testing the three knockout
mice, only the GLT- 1 knockout mice produced current that differed from
that of the control mice.

This means that the greater and faster accumulation of glutamate outside
of neurons resulted from impaired uptake by astrocytes.

"Abnormal glutamate reuptake by astrocytes is just one way overexcite
neurons," says Tanaka. "Nevertheless, if GLT-1 proves to be disrupted
in people who have migraines, drug therapy that acts to increase glial
reuptake of glutamate could be a reasonable therapeutic approach."

========================================================================== Story Source: Materials provided by
Tokyo_Medical_and_Dental_University. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Hidenori Aizawa, Weinan Sun, Kaori Sugiyama, Yukiko Itou, Tomomi
Aida,
Wanpeng Cui, Saori Toyoda, Haruhi Terai, Michiko Yanagisawa,
Kohichi Tanaka. Glial glutamate transporter GLT ‐1 determines
susceptibility to spreading depression in the mouse cerebral cortex.

Glia, 2020; DOI: 10.1002/glia.23874 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200917105337.htm

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