In experiments with mice, scientists from Johns
Hopkins'
Institute for Cell Engineering have discovered the
steps required to integrate new neurons into the brain's
existing operations.
For more than a century, scientists thought the adult
brain could only lose nerve cells, not gain them, but in
fact, new neurons do form during adulthood in all mammals,
including humans, and become a working part of the adult
brain in mice at the very least.
In the first study to show how these "baby" neurons
are integrated into the brain's existing networks, the
Johns Hopkins researchers show that a brain chemical called
GABA readies baby neurons to make connections to old ones.
The discovery is described in the Dec. 11 advance online
section of Nature.
"GABA is important during fetal development, but most
scientists thought it would have the same role it has with
adult neurons, which is to inhibit the cells' signals,"
said Hongjun Song, an assistant professor in the
Neuroregeneration and Repair Program within ICE. "We've
shown that GABA instead excites new neurons and that this
is the first step toward their integration into the adult
brain."
Song added that their discovery might help efforts to
increase neuron regeneration in the brain or to make
transplanted stem cells form connections more
efficiently.
The researchers, including postdoctoral fellows Shaoyu
Ge and Eyleen Goh, discovered that a constant flood of GABA
is required as a first step. Next, the new neuron receives
specific connections that communicate using GABA, which
shifts the constant barrage of GABA in step one to a pulsed
exposure. The third and final step occurs when the new
neuron receives connections that communicate via another
chemical, the critical excitatory messenger glutamate.
In the adult brain, glutamate is the most prevalent
excitatory chemical, and GABA is a major inhibitory
chemical. But it turns out that new neurons are excited by
GABA, whether they are in the fetal brain or the adult
brain, Song said.
"The steps of integration essentially shift the neuron
from being a developing neuron to being an adult neuron.
Initially it's excited by the flood of GABA, but by the
time it's fully integrated, the neuron will respond to GABA
and glutamate like other adult neurons," he said.
The researchers' experiments were done on a part of
the mouse brain called the dentate gyrus, which is thought
to be involved in memory and spatial reasoning, or
navigation. It is one of the few parts of the brain where
new neurons form throughout life and are integrated into
the existing network of cells.
The researchers also figured out why the mouse's new
neurons were excited by GABA: They have greater amounts of
chloride ions, making for a different chemical environment.
By the time they are fully integrated, their chloride
levels have dropped and are similar to other adult
neurons.'
In the mouse experiments, Goh used a technique to
alter the genetics of single cells in order to change new
neurons' ability to accumulate chloride ions (and thus to
manipulate their response to GABA) and to make them glow
with a green protein to ease their identification in the
adult brain. Ge measured the electrical output of the
neurons to establish whether they had become connected to
other neurons.
"Getting new neurons to form connections in other
parts of the brain may be helped through the same steps
that naturally lead to integration in the dentate gyrus,"
Song said.
Among the most likely targets for regeneration or
replacement efforts are the dopamine-producing neurons that
die in Parkinson's disease, muscle-controlling nerves that
succumb in diseases like muscular dystrophy and amyotrophic
lateral sclerosis, or nerves that are damaged by trauma or
injury. In none of these systems are new neurons formed or
integrated to any great extent naturally.
Authors on the report are Ge, Goh, Song, Kurt Sailor,
Yasuji Kitabatake and Guo-Li Ming, all of Johns Hopkins'
Institute for Cell Engineering and the departments of
Neurology and Neuroscience at the School of Medicine. The
researchers were funded by the National Institutes of
Health, the Klingenstein Fellowship Awards in the
Neurosciences, the Whitehall Foundation and the Robert
Packard Center for ALS Research at Johns Hopkins.
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