Transplanting Receptors Allows Study of Their Function

All the highly complicated functions of the human brain ultimately depend on the transmission of electric signals from one nerve cell to another—a sort of passing of the Olympic torch. Neurotransmitters serve as the torch bearers, protein receptors located on the membrane of the receiving nerve cell as their docking sites.

Relatively little is known, however, about the function of these receptors, since there has been no way to study them in living persons.

During the past few years, though, Ricardo Miledi, M.D., a professor of neurobiology at the University of California, Irvine, and colleagues have found a way to study neurotransmitter-receptor function outside the living human brain and in an artificial environment. It is called microtransplantation.

What they do is isolate nerve-cell membranes containing neurotransmitter receptors from a postmortem human brain. They inject the membranes—carrying the original receptors together with any ancillary proteins—into a frog egg. The human nerve-cell membranes fuse with the egg membrane. The human receptors then become functional in their new“ home,” and neurobiologists can then study their properties just as though they were still functioning in a living human brain.

Moreover, the technique works whether neurotransmitter-receptor material is taken from fresh or frozen postmortem brain tissue, Miledi and colleagues reported in the July 21 Early Edition of the Proceedings of the National Academy of Sciences.

This is important, they explained, because “fresh human brain tissues are difficult to obtain [but] frozen postmortem brain tissues ... are available from brain banks all over the world.” Thus their technique opens vast opportunities for neurobiologists to “study the properties of human receptors present in diseased brains” and to learn crucial things about their complicity in various neurological or psychiatric illnesses.

For example, they noted, Italian scientists have used the technique to study the function of neurotransmitter receptors harvested from fresh postmortem brain tissue taken from epilepsy patients. The Italian scientists found an abnormality in the function of GABA receptors taken from this tissue. Miledi's team is using the technique to study the functions of neurotransmitter receptors harvested from frozen postmortem brain tissue taken from persons with autism.

They have already found, for instance, that the temporal lobes of brains of individuals with autism seem to contain a greater number of functional GABA and glutamate receptors than the temporal lobes of control brains do. This may be because the cerebral cortexes of autistic brains are known to contain more neurons than the cerebral cortexes of control brains. They have also found that the situation seems to be more complex in the cerebellum: some autistic cerebella seem to contain fewer functional GABA and glutamate receptors than control cerebella do, whereas others seem to contain more.

“Because of the multiple origins and symptoms of the autism spectrum disorders, we are fully aware that it is necessary to study many more brains and tissues from many areas,” they pointed out. Nonetheless, they asserted, it is “already sufficiently clear” that their microtransplantation technique “will help to determine in great detail the type, number, and functional properties of autistic neurotransmitter receptors....”

Miledi and his team likewise foresee that neurotransmitter receptors harvested from frozen, diseased brain tissue and reactivated with their microtransplantation technique can be used to “develop novel medicinal drugs.” In fact, the Italian group is using its discovery of a GABA-receptor abnormality in epilepsy to try to find new medications for epilepsy, Miledi told Psychiatric News.

Anthony Phillips, Ph.D., director of the University of British Columbia Institute of Mental Health in Canada, and his colleagues are using neurotransmitter receptors to develop a new generation of psychotropic drugs that target much more selectively the regulation of neurotransmitter receptors in the brain than current psychotropic drugs do (Psychiatric News, January 6, 2006). In essence, one of their drugs would not block a receptor or activate a receptor, as current psychotropic medications do, but would influence the movement of receptors in and out of the membranes of nerve cells. Phillips told Psychiatric News that he does not foresee the microtransplantation technique developed by Miledi and his group having an immediate application to his group's work. Nonetheless, he considers the technique an “exciting new development.”

The research conducted by Miledi and his colleagues was funded by the Harvard Brain Tissue Resource Center, National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders, and American Health Assistance Foundation.

An abstract of “Microtransplantation of Neurotransmitter Receptors From Postmortem Autistic Brains to Xenopus Occytes” is posted at<www.pnas.org/content/early/2008/07/18/0804386105>.▪