Science Daily (Jan. 28, 2008) - Scientists have discovered that mice genetically engineered to lack a particular protein in the brain and have profound deafness, seizures. The finding suggests a pathway, they say, for exploring the causes of hereditary deafness in humans and epilepsy.
More broadly, the discovery provides an entry point for resisting new insight into the role of glutamate, the chemical messenger carried by the protein, says the team, led by scientists at the University of California, San Francisco. Glutamate is involved in virtually every brain function, including sensory imagination, learning and memory.
The missing protein is a particular "vesicular transport neurotransmitter," a machine nerve cells within that ferry chemical messengers, or "neurotransmitters," from the fluid-filled vesicles into cytoplasm that are positioned at the tips of nerve cells and serve to release onto neurotransmitters Neighboring Cells. Carrier neurotransmitters and work together to make all possible neural communication essentially in the brain.
While the neurotransmitter glutamate is the major excitatory messenger in the brain, the neurotransmitter GABA is the major inhibitory messenger, sending signals that reduce agitation and anxiety. Two other neurotransmitters, dopamine and serotonin, modulate the activity of neural circuits influence mood to sleep and other aspects of behavior.
Scientists have known for several years about two vesicular glutamate transporters, VGLUT1 and VGLUT2. As would be predicted, they are expressed on nerve cells that release glutamate. More recently, scientists have identified VGLUT3. To their surprise, they have discovered that VGLUT3 is primarily expressed by nerve cells that GABA release, acetylcholine and serotonin, another neurotransmitter. VGLUT3 is also released in some non-nerve cells, tissues outside the brain. These findings led scientists to suspect that might VGLUT3 support function, other than some neurotransmission.
In the current study, published in the Jan 24, 2008 issue of Neuron, the team explored the role of VGLUT3 in mice genetically engineered to lack the forwarder. The effect was dramatic.
"Mice lacking the shipper are completely deaf from birth," says the senior author of the study, Robert Edwards, MD, professor of neurology and physiology at University of California, San Francisco. "Moreover, they had significant seizures.
As the gene encodes VGLUT3 that is known to have sequence changes in humans, it is possible that these or other changes may be the underlying cause of deafness or epilepsy in humans, according to the research. They plan to screen people with these conditions for changes in the gene vglut3, says the first author of the study, Rebecca Seal, PhD, post a fellow in the laboratory Edwards
In addition, because the mice in the study lacked the protein in all cells that would normally make it, the team plans to make a "conditional knockout", in which the gene is inactivated only in specific types of nerve cells. This will reveal which VGLUT3 nerve cells expressing a particular account for brain function.
At the outset of the study, the team VGLUT3 knew that was expressed during brain development by a population of inhibitory GABAergic-brainstem in the pathway that transmits information about sound. They suspected that the absence of VGLUT3 - which would allow the release of the excitatory glutamate - might produce a subtle defect in sound localization. Instead, the animals were completely deaf.
The explanation, they learned, was that VGLUT3 contributes to the release of glutamate at a key point in the production of sound. It turns out that inner hair cells of the cochlea, which are known to convert the auditory input, or signal, glutamate release, VGLUT3 express, transporters and contributes to the release of the first onto glutamate neurons in the pathway that carries into the sound Brain. Without VGLUT3, No. glutamate that is released at synapses.
The scientists also knew that from the outset VGLUT3 is expressed by a subset of - in the hippocampus and cortex that are known to release the inhibitory transmitter GABA. The presence of these VGLUT3-might also suggested that the release excitatory glutamate. Since inhibitory-contribute to a range of brain wave oscillations active, the team hypothesized that the disruption of these systems might affect brain wave activity in the cerebral cortex.
In fact, EEG (electroencephalograph) revealed that all of the mice had seizures, and even when they were having full-blown attacks they had electrical discharges in abnormal brain, known as "epilepiform activity. Surprisingly, the seizures - which last Up to two minutes - were accompanied by little or no change in behavior.
The team plans to screen young patients with hereditary or early-onset epilepsy to see if they have changes in this protein, says Edwards.
Since VGLUT3 may be required for relatively subtle aspects of behavior elicited not easily in a mouse, the research would also like to study and identify human patients, according to Edwards. Neuromodulatory The effect of glutamate release by serotonin, he says, may be easier to detect in humans.
"If we found lacking VGLUT3 patients," he says, "we could carry out psychological testing, which in turn would give us an idea why most serotonin and glutamate release.
"This is a case of a mouse model to patients leading us who will, in turn, suggest additional roles for functional glutamate that we can test in the mouse. The results will help us to understand basic brain function and how it goes awry in Disease . "
Other co-author of the study were Omar Akil, UCSF Department of Otolaryngology, Eunyoung Yi, Johns Hopkins School of Medicine, Christopher M. Weber, UCSF Department of Otolaryngology, Lisa Grant, Johns Hopkins School of Medicine; Jong Yoo, Baylor School of Medicine; Amanda Clausewitz, University of Pittsburgh, Karl Kandler, University of Pittsburgh, Jeffrey L. Noebels, Baylor School of Medicine, Elisabeth Glowatzki, Johns Hopkins School of Medicine and Lawrence R. Lustig, UCSF Department of Otolaryngology.
The study was funded by the National Alliance for Research on Schizophrenia and Depression and by several institutes of the National Institutes of Health, including the Institute of Mental Health, Neurological Disorders and Stroke, Child Health and Human Development and Drug Abuse.
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