Researchers Make Surprise Discovery That Brain Cells Can Transmit Three Signals At Once

Just as surprising, they report in the lead article of this month’s Nature Neuroscience, is that by definition these three neurotransmitters are seemingly at odds with each other. One, glutamate, is a textbook excitatory neurotransmitter; while the other two, GABA and glycine, are quintessential inhibitory neurotransmitters.

Information is transmitted between neurons when one cell releases a neurotransmitter at a synapse, the point of contact between cells. When released from a cell, neurotransmitters are sent on a one-way ride that dead ends at the membrane of the adjacent cell. Like lock and key, they bind to specific receptors on the surface of the receiving cell, causing its electrical activity to be enhanced or inhibited.

The first week after birth marks a critical phase in the developing rat brain, a time period comparable to three months gestation in a human, when neurons are meticulously organizing and self-selecting to assemble into specific brain structures and neuronal networks. It has long been known that a specific receptor for glutamate, the NMDA receptor, plays a crucial role in these processes, but how inhibitory synapses, which account for about half of the brain’s cellular connections, would gain access to these receptors has long puzzled researchers. But now, the Pittsburgh researchers believe they have solved some of the mystery. During this crucial period, immature inhibitory synapses also release the excitatory neurotransmitter glutamate, and by mimicking excitatory synapses, can stimulate NMDA receptors.

“It first appeared odd to us that an immature inhibitory synapse would want to release an excitatory neurotransmitter. After all, this contradicts the most basic principles that have defined the field of neuroscience. But when we also found that this glutamate activates NMDA receptors at the most critical stage of brain development and organization, we realized that this could explain a number of fundamental questions,” explained Karl Kandler, Ph.D., associate professor of neurobiology at the University of Pittsburgh School of Medicine, and the study’s senior author.

“These findings shed new light on how inhibitory synapses evolve and are assembled into functional circuits in the developing brain,” he added.

Many brain disorders, like epilepsy, schizophrenia and depression, involve deficits that prevent normal inhibition of cells. Dr. Kandler’s research could eventually provide insight into the biological cause of these disorders and help to identify novel approaches for prevention and treatment. Further study could have particular implications for dyslexia and tinnitus – often referred to as ringing in the ears – which can be caused by abnormal inhibitory signaling within the auditory system, a region of the brain that is the focus of Dr. Kandler’s research.

Before there can be practical clinical applications several questions need to be answered, including how GABA, glycine and glutamate synapses cooperate to activate NMDA receptors. In the traditional sense, when inhibitory synapses are mature, they would never release glutamate, nor would they be able to depolarize a cell, both of which are required for NMDA receptor activation. But, as if by design, during the exact period when the auditory brain is undergoing refinement, the GABA and glycine neurotransmitters can produce depolarizations, a process that normally can only be achieved by excitatory transmitters.

It is not yet known how long the cells retain this unique capacity, for how long the neurons are able to release all three neurotransmitters or what causes the cells to stop releasing glutamate as they mature. But according to the study’s first author, Deda C. Gillepsie, Ph.D., a post-doctoral associate working with Dr. Kandler, things become more normalized within three weeks of birth, or about one week after hearing is fully developed. So, perhaps early auditory experience provides the signals that stop the cells from releasing glutamate, which is a prerequisite for correctly processing auditory information.

“It will be interesting to find out whether abnormal hearing, such as partial deafness or hearing dominated by noise, which in humans can affect normal language development, would cause glutamate to still be released. Finding such an association would be intriguing, but for now this remains just an hypothesis that will require much study, Dr. Gillespie said.

The third author of the study is Gunsoo Kim, Ph.D., who is now pursuing post-doctoral studies at the University of California, San Francisco.

Their research was supported by the National Institute on Deafness and Other Communication Disorders and the National Institute of Neurological Disorders and Stroke, both of the National Institutes of Health.