Immune molecules prune synapses

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Science 14 December 2007:

Vol. 318. no. 5857, pp. 1710 - 1711

DOI: 10.1126/science.

318.5857.1710a

News of the Week

NEUROBIOLOGY:

Immune Molecules Prune Synapses in Developing Brain

Greg

The complement cascade is part of the body's innate immune defense: a

protein work crew whose duties include tagging bacteria and other bad

guys for elimination. A new study suggests that complement proteins may

have a surprising yet analogous function in the developing brain,

tagging unwanted synapses for removal. The work also hints that these

proteins may promote synapse loss in early stages of neurodegenerative

disease.

Early indicator. C1q (green) can be seen early in glaucoma (left), even

before synapses (red) and neurons (blue) disappear as the disease

progresses (right).

CREDIT: B. STEVENS ET AL., CELL 131, 1-15 (14 DECEMBER 2007) 2007

ELSEVIER INC.

" It's a pretty provocative finding, " says Greg Lemke, a neurobiologist

at the Salk Institute for Biological Studies in San Diego, California.

" This is part of a growing body of evidence that many molecules of the

immune system have a second set of jobs in the brain, " says

Boulanger, a neurobiologist at the University of California, San Diego.

The new study, which appears in the 14 December issue of Cell, began as

an attempt to determine whether neural support cells called astrocytes

have a role in refining synaptic connections between neurons during

development, says senior author Ben Barres of Stanford University in

Palo Alto, California. Postdoc Beth s and colleagues used gene

chips to look for changes in gene expression in neurons from the

developing retinas of rats when the neurons were cultured with astrocytes.

To their surprise, astrocytes spurred the neurons to crank out a

complement protein called C1q, which elsewhere in the body kicks off a

cascade of chemical events that culminates in the destruction of an

intruding cell. In experiments with mice, the researchers found that C1q

concentrations in the retina and brain peaked a week or so after birth

and dropped dramatically as mice matured. The peak coincided with the

period when unwanted synapses are pruned. More intriguing, C1q seemed to

concentrate at puny, immature-looking synapses in the developing nervous

system.

When the researchers examined the brains of mice lacking a functional

C1q gene, they found that development had gone awry in the lateral

geniculate nucleus, a relay station in the brain that receives synaptic

inputs directly from retinal neurons. In normal mice, geniculate neurons

initially receive inputs from both eyes and then prune them so that they

only receive input from one eye or the other. In the mutant mice,

geniculate neurons maintained extraneous inputs from both eyes into

adulthood.

That's a striking finding, Boulanger says: " When you get rid of these

proteins that we thought just functioned in the immune system, it

disrupts a very specific event that we think is involved in making the

precise, final connections in the developing visual system. " Many

questions remain, however. Barres suspects that complement proteins mark

unwanted synapses for removal by microglia, immune cells in the brain.

More work is needed to demonstrate that, Boulanger says, and to figure

out why only certain synapses are flagged for removal.

Finally, Barres and colleagues collaborated with Simon 's group at

the Laboratory in Bar Harbor, Maine, to investigate whether C1q

might have a role in synapse loss in a mouse model of glaucoma. Compared

to normal adult mice, adult glaucoma mice exhibited elevated C1q levels:

The protein accumulates at retinal synapses early in the disease, even

before synapses disappear and neurons die off.

Synapse loss precedes cell death in Alzheimer's and other

neurodegenerative diseases, Barres notes. He speculates that drugs that

block the complement cascade may forestall neurodegeneration in a number

of disorders. It's an exciting idea, says Vetter, a

neurobiologist at the University of Utah in Salt Lake City: " There's

good evidence that these complement components are upregulated in other

diseases. "