Research Identifies Proteins Crucial to Construction of Brainís Information Superhighway
Communication in the brain travels from one nerve cell to another
through critical connections called synapses. These neuron-to-neuron
junctions form early in brain development, and their construction
was thought to be guided by the nerve cells themselves. Now, investigators
supported by the National Institute on Drug Abuse (NIDA), National
Institutes of Health, have discovered that cells called glia, known
to provide support for neurons in the mature brain, also play a
crucial role in formation of synapses during the surge of development
following birth. This key insight into the process of normal synapse
development may lead to improved treatment of conditions such as
drug addiction and epilepsy, which are characterized in part by
too many synapses. The research, led by Dr. Ben Barres of Stanford
University School of Medicine in Stanford, California, is reported
in the February 11, 2005 issue of the journal Cell.
“Synapses are the key connections between cells in the brain. We know that
drugs alter these connections, and that the developing brain is vulnerable to
addictive drugs’ disruption of normal communication,” says NIDA Director
Dr. Nora D. Volkow. “Compounds that direct synapse formation may offer
a therapeutic option for people fighting drug addiction or other neurologic conditions.”
Glia account for 90 percent of the cells in a mammalian brain, but until recently
scientists focused mainly on the supportive role that glial cells play in helping
mature neurons survive. Dr. Barres, along with Stanford postdoctoral fellows
Dr. Karen Christopherson and Dr. Erik Ullian, developed a method for growing
neurons in a laboratory without glial cells. Then they isolated proteins produced
by glial cells and observed the effect when they added the proteins to a culture
of neurons. Two of the proteins, thrombospondin 1 and 2, led to the development
of synapses albeit functionally incomplete ones.
The synapses that developed in Dr. Barres’ laboratory dish in the presence
of thrombospondin were able to transmit signals but were unable to receive them.
In other words, the neuron transmitting the signal is able to secrete a chemical
messenger called a neurotransmitter but the neighboring neuron receiving the
signal is unable to detect the presence of the neurotransmitter. Because completely
functional synapses occur in the presence of glia, “we know that glia produce
at least one other protein, which we have not yet identified, that is necessary
to produce a fully functional synapse,” Dr. Barres says. This yet unidentified
protein enables the receiving neuron to detect the neurotransmitter sent from
the neuron transmitting signal when synapses form.
To help confirm the role of the thrombospondins in synapse development, the scientists
next developed a strain of mice that lacked the ability to produce thrombospondins
1 and 2; the brains of these mice had 40 percent fewer synapses than normal mice.
Interestingly, glia only secrete these thrombospondins early in brain development,
concurrent with the normal formation of synapses. These new findings raise the
possibility that the relatively poor ability of the adult brain to form new synapses
may be due to the low levels of the glial thrombospondins.
“Fully understanding the contribution made by glial thrombospondins could
make possible the development of thrombospondin-based therapies to stimulate
and direct synapse formation,” notes Dr. Volkow.
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 more than
85 percent of the world’s research on the health aspects of drug abuse
and addiction. The Institute carries out a large variety of programs to ensure
the rapid dissemination of research information and its implementation in policy
and 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 http://www.drugabuse.gov.