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.
From left: Jorge Mauricio Reyes-Ruiz, Ph.D., Agenor Limon, Ph.D., and
Ricardo Miledi, M.D., of the University of California, Irvine, have found a
way to study neurotransmitter-receptor function outside the living
Credit: Ricardo Miledi, M.D., et al.
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
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.
This is a high-resolution photo of several frog eggs containing
functional human GABA receptors. Superimposed on the photo is a trace of a
GABA electric current generated by the receptors.
Credit: Ricardo Miledi, M.D., et al.
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
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