Key insight into the process of normal synapse development may lead to improved treatment of conditions such as drug addiction and epilepsy

Feb 13 2005

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.