Boosting The Synapses By Stopping A Receptor Called 'Nogo'

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Boosting The Synapses By Stopping A Receptor Called 'Nogo'

http://www.medicalnewstoday.com/articles/101095.php

New findings about a protein called the nogo receptor are offering

fresh ways to think about keeping the brain sharp.

Scientists have found that reducing the nogo receptor in the brain

results in stronger brain signaling in mice, effectively boosting

signal strength between the synapses, the connections between nerve

cells in the brain. The ability to enhance such connections is

central to the brain's ability to rewire, a process that happens

constantly as we learn and remember. The findings are in the March 12

issue of the Journal of Neuroscience.

The work ties together several research threads that touch upon the

health benefits of exercise. While those benefits are broadly

recognized, how the gains accrue at a molecular level has been

largely unknown. The new research gives scientists a way to produce

changes in the brain that mirror those brought about by exercise, by

reducing the effect of the nogo receptor.

The find comes as a surprise, because for much of the last decade,

the nogo receptor has been a prime target of researchers trying to

coax nerves in the spinal cord to grow again. They named the protein

after its ability to stop neurons from growing. Its action in the

brain has not been a hot topic of study.

The find by neuroscientists at the University of Rochester Medical

Center casts the nogo receptor in a new light. Instead of serving as

a target for efforts at regrowing spinal nerve fibers - indeed, the

Rochester team showed last year that the molecule doesn't control

that process - the molecule suddenly has much broader implications

for learning and memory.

" One of the central questions in neuroscience is - what is the

molecular and cellular basis of learning? " said Roman Giger, Ph.D.,

associate professor in the Department of Biomedical Genetics, who led

the study. " The nogo receptor seems to play a role. "

The receptor is a promiscuous molecule that hooks up with several

other molecules which prevent the growth of neurons in the spinal

cord. For most of this decade, scientists have worked to target the

molecule, thinking that if they could block it, they could possibly

regenerate nerves, repairing spinal cord damage in a way that is

impossible today.

But that road has proved difficult. Last year in the same journal,

the Rochester team led by Giger showed that while the nogo receptor

does play a role in preventing spinal nerves from growing, it does

not control the process outright. While nogo receptor activation can

transiently stunt the growth of neurons, it is not required for

chronic outgrowth inhibition of injured nerve cells.

Giger's team has found that in some areas of the brain, such as the

hippocampus, the nogo receptor is at least 10 times more prevalent

than in the spinal cord.

In the brain, Giger's team found that the nogo receptor wields broad

influence over a process known as neuroplasticity, which describes

how our brain cells change and adapt constantly to meet our needs. It

can be thought of simply as the brain's ability to rewire itself on

the fly to meet the demands of an organism. The process explains why

people are able to recover many of their abilities even after a

traumatic brain injury or a stroke: Other brain cells pick up the

work for the ones that have died.

Giger's team found that the nogo receptor plays an important role in

changing the brain in two ways.

First, the molecule plays a completely unexpected role manipulating

the strength of signals between brain cells in the synapses. A team

led by Shrager, Ph.D., professor of Neurobiology and Anatomy,

made sophisticated measurements of the strengths of the signals as

they passed from cell to cell in mice. They found that mutant mice

with fewer nogo receptors than normal had stronger brain signaling,

what scientists call " long-term potentiation.

The molecule also affected tiny structures known as dendritic spines,

crucial connections that are extensions of the neuron and help

cells " talk " to other cells. Mice with lots of the nogo receptor had

a different mix of dendritic spines than normal mice. In the

hippocampus, the mutant mice had fewer mushroom-shaped dendritic

spines and more stubby and thin spines than the other mice.

Scientists don't yet know the ramifications of the change, but they

say it's firm evidence that the nogo receptor has effects on the

anatomic structure of the brain. Creation and removal of dendritic

spines is an important form of brain rewiring.

The team attributes much of the effects of the nogo receptor to its

ability to strongly bind to a growth factor known as FGF2 (fibroblast

growth factor 2), which in the brain and other parts of the central

nervous system nourishes neurons, allowing them to branch out and

grow new sprouts. When the nogo receptor is present in abundance, it

binds to FGF2 molecules, and as a result neurons no longer branch and

sprout as they otherwise would.

Altogether, the findings show that the nogo receptor has a broad

impact on processes in the brain that underlie learning and memory,

said Giger.

" It's known that changes in synaptic strength can lead to rewiring of

the nervous system in such a way that we can compensate for mild to

moderate injuries, " said Giger, who is a scientist in the Center for

Neural Development and Disease. " Enhancing synaptic plasticity can

partially counter the effects of an injury like stroke, or traumatic

brain injury. Really, the process happens routinely in many stroke

patients - it's what makes rehabilitation after stroke possible. "

Much of the same type of rewiring also happens as a result of

exercise. Scientists have shown that exercise improves the brain's

neuroplasticity, boosting the brain's ability to sprout new

structures and send crisp signals, which in turn helps people recover

from injuries to the central nervous system. And recently,

researchers at the Karolinska Institute in Stockholm showed that

exercise reduces the abundance of the nogo receptor in the brain.

Giger's work provides a molecular framework that brings the disparate

findings together.

The findings could also explain something that has puzzled

scientists, said Giger. Mice with damaged spinal cords that have been

treated with compounds designed to knock out the nogo receptor seem

to improve a bit, even though scientists have never been able to

demonstrate nerve regrowth in those mice. It may be that their

improvement instead is coming through the signal-boosting effect in

the synapses.

While it's tempting to think that knocking down the nogo receptor is

a simple process that would help people under all circumstances by

boosting their brain power, Giger points out that the molecule is not

only found at synapses but also along axons, where scientists believe

it plays an important role limiting the sprouting of nerve fibers.

Any effort to reduce the nogo receptor will have to be studied

thoroughly to watch for other effects.

The work was funded by the National Institute of Neurological

Disorders and Stroke, the New York State Spinal Cord Injury Research

Program, and the Dr. Miriam and Sheldon G. Adelson Research Medical

Foundation's Adelson Program in Neural Repair and Rehabilitation.

While Giger headed the project, much of the research was done in

equal part by the two first authors, Research Assistant Professor

Hakjoo Lee, Ph.D., and graduate student Raiker.

Other authors include former graduate student Karthik Venkatesh,

Ph.D., now at the University of Michigan; former Professor Hermes

Yeh, Ph.D., now at Dartmouth; technician Geary; graduate

student Laurie Robak; and Yu Zhang, Ph.D., now a research assistant

professor in the Department of Neurosurgery.