Early Fine-Tuning of Neural Connections May
Turn Destructive Later in Life
Mouse study implicates immune process in brain development as
well as degenerative diseases
The immune system helps to prune excess connections between neurons
in the developing brains of young mice, according to scientists
funded by the National Institute on Drug Abuse (NIDA), part of
the National Institutes of Health (NIH). The study, published in
the December 14 issue of the journal Cell, sheds critical
new light upon a fundamental process, while hinting at a likely
mechanism behind neurodegenerative diseases like glaucoma and Alzheimer's
disease.
Shortly after birth, the mammalian brain contains vast numbers
of connections, or synapses, between neurons — many more
than will be needed in adulthood. Scientists have known for years
that the developing brain follows a use it or lose it rule: inactive
connections are pruned away during childhood and adolescence. However,
the molecular mechanism underlying this pruning process has remained
one of the biggest mysteries in neurobiology. Now, Dr. Beth Stevens
and Dr. Ben Barres of the Stanford University School of Medicine
and their colleagues report that a protein used by the immune system
to destroy bacteria is also needed by the young brain to target
and destroy unwanted synapses.
"From the fetal period through early adulthood, the developing
brain is constantly fine-tuning its synaptic connections. These
results provide new insight into this vital process," said
Dr. Nora Volkow, NIDA director. "Eventually, research like
this, into the fundamental mechanisms of brain development, will
help us understand why a child's brain is so vulnerable to environmental
factors, including addictive drugs."
"The immune system's involvement in sculpting synapses was
totally unexpected," added Dr. Barres. The immune protein
C1q is among the body's first responders to injury or infection,
attaching to dead cells or bacteria and triggering their destruction.
Surprisingly, the researchers also found C1q attached to immature
synapses in the brains and retinas of young mice. Unlike normal
mice, mice missing C1q were unable to eliminate extra synapses
as they aged, producing disorganized, abnormal connections in their
visual systems.
In collaboration with Dr. Simon John of The Jackson Laboratory,
the researchers asked whether diseases like glaucoma could trick
C1q into targeting synapses in the adult. They found that although
C1q is normally turned off in the nervous systems of mature mice,
it reappears during the early stages of glaucoma, when retinal
synapses begin to deteriorate. This discovery offers a tantalizing
clue to how synapses might be lost in neurodegenerative diseases
like Alzheimer's disease and ALS.
"It looks like as soon as something goes wrong, C1q is reactivated," said
Dr. Barres. "In the mouse model of human glaucoma, C1q is
the earliest sign of disease, appearing well before visible damage
to synapses and neurons. We hope that if we block C1q and the immune
cascade it triggers, we can block the disease before neurons start
to die."
The National Institute on Drug Abuse is a component of the National
Institutes of Health, U.S. Department of Health and Human Services.
NIDA supports most of the world's research on the health aspects
of drug abuse and addiction. The Institute carries out a large
variety of programs to inform policy and improve practice. Fact
sheets on the health effects of drugs of abuse and information
on NIDA research and other activities can be found on the NIDA
home page at www.drugabuse.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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