EVIDENCE FOUND FOR NOVEL BRAIN CELL COMMUNICATION WITH IMPLICATIONS FOR EPILEPSY, PSYCHOSIS AND OTHER FIELDS
Jul 16, 2007
Embargoed until 5:00 p.m., Monday, July 16, 2007
Contact: Ron Najman – 718-270-2696
ron.najman@downstate.edu
Dell Rae Moellenberg – 970-491-6009
dellrae.moellenberg@colostate.edu
Discovery Suggests First New Model of Brain Function Since 1940s
An article published today, July 16, 2007, in Proceedings of the National Academy
of Sciences provides strong evidence for a novel type of communication between nerve
cells in the brain. The findings may have relevance for the prevention and treatment
of epilepsy, and possibly in the exploration of other aspects of brain functions,
from creative thought processes to mental illnesses such as schizophrenia.
The work was performed jointly by scientists at SUNY Downstate Health Sciences University
in Brooklyn, New York; Colorado State University in Fort Collins, Colorado; Mount
Sinai School of Medicine in Manhattan, New York; and the University of Newcastle in
the United Kingdom. The lead author was Dr. Farid Hamzei-Sichani, an MD/PhD student
at Downstate Medical Center, working in the laboratory of Roger Traub, MD, professor
of physiology and pharmacology and of neurology at SUNY Downstate.
Epilepsy – a group of disorders characterized by the recurrent occurrence of spontaneous
seizures – affects roughly one-half of one percent of the U.S. population, and a higher
percentage still in developing countries. In approximately one-third of patients,
seizures are not properly controlled by available treatments. Problems can arise
in the ability of patients to function at home and in society.
Epileptic seizures are customarily regarded to reflect an imbalance between the ability
of nerve cells to excite one another, on the one hand, and to inhibit one another,
on the other hand. The excitation and inhibition take place because the activity
of nerve cells leads to the release of particular chemicals – called neurotransmitters
– at specialized junctions that are called “chemical synapses”. The neurotransmitters
diffuse across a tiny space between the nerve cells, and then bind to proteins (called
“receptors”) on other nerve cells. Binding of a neurotransmitter to a receptor in
turn causes excitation or inhibition in the other nerve cells.
This is the “classic” means of communication between nerve cells, and lies at the
base of most of current understanding of how the brain processes information and controls
muscles in the body.* A seizure is presumed to occur when there is too much chemical
synaptic excitation, and/or not enough inhibition.
There is, however, another means for nerve cells to communicate with one another,
called gap junctions. Gap junctions allow electric current to flow directly from
one cell to another, without involving the release and diffusion of transmitter chemicals,
and may be thought of as “short circuits” linking or cutting across the pathways through
which cells normally communicate.
Gap junctions are found in many parts of the body, such as the heart. Gap junctions
between nerve cells have been most studied in older vertebrates (such as fish) and
in invertebrates (such as leeches and crabs); additionally, gap junctions in mammals
have been studied that exist between nerve cells that produce inhibition – that is,
between cells that are not primarily involved in epileptic seizures. Gap junctions
between excitatory cells in the mammalian brain have not traditionally been part of
the thinking of neuroscientists.
One source of the idea that gap junctions were vitally important in epilepsy came
from observations of brain waves that are recorded just before a seizure begins: these
waves can occur at very high frequencies, 100 times per second or even more. That
observation, and other experiments performed in Europe starting 10 years ago, led
one of the authors of the PNAS article (Roger Traub, at SUNY Downstate) to propose
a novel hypothesis: that excitatory nerve cells – the cells most critical in the generation
of epileptic seizures – are also coupled together by gap junctions; that is, gap junctions
are not confined to the cells that produce inhibition. Furthermore, gap junctions
between excitatory cells were predicted to occur at an unexpected place: the axons
of the cells (the axon is the part of the cell that allows propagation of a signal
over long distances).
Such an hypothesis was naturally controversial. Scientists wanted to see these proposed
gap junctions. But the gap junctions are tiny, and seeing them requires the use of
an electron microscope, an instrument able to resolve structural details that are
smaller than the wavelength of visible light – details on the scale of tens of Angstroms
(an Angstrom is roughly the diameter of a hydrogen atom). Application of the electron
microscope to examine tiny structures in nerve cells is a special interest of Dr.
Patrick Hof of the Mount Sinai School of Medicine, another of the PNAS authors. Furthermore,
in the study of gap junctions, use of the electron microscope is often joined with
chemical (antibody) techniques that allow one to determine which proteins are present
within the junctions. Such techniques were pioneered by Dr. John Rash of Colorado
State University, and applied by Dr. Naomi Kamasawa in Dr. Rash’s laboratory: both
are also authors of the PNAS article.
The PNAS article by Hamzei-Sichani et al. provides the first electron microscopic
evidence (or “ultrastructural” evidence) for gap junctions on the axons of excitatory
nerve cells in the mammalian brain. Gap junctions at this site, on axons, would be
expected to act as short circuits for nerve signals and to produce “cross-talk.”
The new data raise the provocative question as to whether cross-talk is an aspect
of normal brain function.
What are the implications for epilepsy? First, more needs to be learned about the
distribution of gap junctions – what nerve cells have them, where on the cells are
they located, and how are they controlled (i.e. can the gap junctions be opened or
closed by chemical signals)? Second, more needs to be learned about exactly how gap
junctions contribute to the very fast brain waves that can presage a seizure. And
finally, it needs to be determined if attenuating or preventing these very fast brain
waves can prevent seizures. As is virtually always the case in biomedicine, each
discovery creates the need for more experiments.
What is clearly the case, however, is that a whole new direction is opening up in
understanding the origins of epilepsy, and in conceiving of new approaches to treatment
and prevention.
* The classic model of how brain cells communicate was put forth in 1943 by Warren
McCulloch and Walter Pitts, at the time the first digital computers were being envisaged,
and the McCulloch-Pitts model suggested that brain cells communicate in a binary fashion,
represented by a “1” for firing and a “0” for not firing, much as a modern computer
functions.
While it is common to say that a mammalian brain functions like a computer, this is
a somewhat faulty idea, in part because the observation from the Traub lab suggests
that gap junctions cause “short circuiting” as part of the brain’s normal functions.
(A real computer could not function if it short circuited.) It is possible that these
short circuits in the mammalian brain generally enhance brain function and adaptation
to the environment, such as by permitting creative thinking, the combining of isolated
facts into new ideas.
Additionally, Dr. Jeremy Coplan, a professor of psychiatry at SUNY Downstate –- has
proposed that excessive firing of these circuits along gap junctions may play a role
in psychosis and mania.
Dr. Traub recently won Germany’s prestigious Humboldt Research Award. He received
his A.B. in 1967 in Mathematics from Princeton University. He then attended the University
of Pennsylvania where he earned an M.D. in 1972. He completed his internship in Medicine
at the University of Pennsylvania a year later. In 1981 he completed his residency
in Neurology at the Neurological Institute of New York.
He has authored more than 100 articles. He has co-authored two books: “Fast Oscillations
in Cortical Circuits with John G.R. Jefferys and Miles A. Whittington, MIT press 1999;
“Neuronal Networks of the Hippocampus” with Richard Miles, Cambridge University Press
1991. He is working on a new book “Cortical Oscillations in Health and Disease with
Miles A. Whittington. That book will be published next year by Oxford University Press.
For more than 30 years, Dr. Traub has dedicated his work to finding a new approach
to treat and cure epilepsy, an illness that affects more than 1 million people in
the United States and millions more across the world.
John Rash, a professor at Colorado State University in the College of Veterinary Medicine
and Biomedical Sciences, runs the only laboratory in the world that can directly visualize
and label the proteins in gap junctions of neurons and map their exact location in
the brain. In addition, the laboratory devised a complex mapping system to pinpoint
the exact location of the gap junctions on individual neurons in the brain. Rash and
a team of researchers at the university within the Biomedical Sciences Department
developed technology to use antibodies to target and attach microscopic beads of gold
to gap junction proteins. Highly visible under an electron microscope, the gold beads
confirm the presence of gap junctions and simultaneously identify the specific gap
junction proteins. The mapping project is cumbersome but necessary to identify the
specific functions of neurons and their supporting cells. Researchers spend about
100 hours mapping an ultra-thin replica of tissue section. The replica is about the
width of a Times Roman 12 point zero printed on a piece of paper, but paper is 50,000
times thicker than the replica.
###
About SUNY Downstate Health Sciences University
Downstate Health Sciences University in Brooklyn is one of four academic health centers (AMCs) in The State University of New York (SUNY) 64-campus system and the only SUNY AMC in New York City dedicated to health education, research, and patient care for the borough’s 2.7 million residents. Its flagship hospital, University Hospital at Downstate (UHD), is a teaching hospital and benefits from the expertise of Downstate’s exceptional medical school and world-class academic center research facilities. With a staff of over 800 physicians representing 53 specialties and subspecialties, Downstate offers comprehensive healthcare services to the community.
UHD provides high-risk neonatal and infant services, pediatric nephrology, and dialysis for kidney diseases and is the only kidney transplantation program in Brooklyn. Beyond its clinical expertise, Downstate houses a range of esteemed educational institutions, including its College of Medicine, College of Nursing, School of Health Professions, School of Graduate Studies, and School of Public Health. Downstate fosters innovation through its multifaceted biotechnology initiative, the Biotechnology Incubator and BioBAT, which support early-stage and more mature biotech companies.