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| Figure 1 (left): Phase-contrast photomicrograph of nerve cells showing their long-transmitting (axonal) ends and stubbier signal-receiving (dendritic) ends, which meet at special junctions called synapses. | |
| Figure 2 (right): Fluorescent micrograph of two nerve cells that express green fluorescent protein (GFP), showing their long axonal and bush-like dendritic ends. | |
The human brain is composed of more than a trillion (1012) nerve cells whose signal-carrying protrusions (the long axons and stubbier dendrites of Figures 1 and 2) are interconnected at special points of contact called synapses. When an electrical signal reaches the axonal side of a synapse, it triggers the release of small vesicles full of neurotransmitter molecules, such as acetylcholine or glutamate. When these molecules diffuse to the dendritic side of the synapse, they alter the physiological state of the receiving nerve cell, creating a new electrical signal which again propagates onward. Synapses are thus the basic information processing units of the vertebrate brain. The modulation of neurotransmitter release and the formation of new synapses account for the plasticity of the brain, which permits learning, memory and the alteration of behavior. Little, however, is known about the molecular and cellular mechanisms that contribute to synapse formation and plasticity.
Dr. Uri Ashery and his TAU colleagues from the Department of Neurobiochemistry are studying the molecular and cellular mechanisms that underlie neuronal communication, using molecular biology, electrophysiology, imaging and computer simulation techniques. They have already discovered several key proteins involved in synaptic transmission in nerve cells and in neuroendocrine cells. They found that Munc13-1 is a key protein in facilitating neurotransmitter release. They further demonstrated that inserting and expressing additional copies of the Munc13-1 gene enhances the release of neurotransmitter-containing vesicles. Since the level of Munc13-1 protein can alter synaptic transmission, it may also account for synaptic plasticity processes.
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| Figure 3: Munc13-1 protein molecules tagged with green fluorescent protein (GFP) move from the cytoplasm to a neuroendocrine cell membrane in response to stimulation. |
Electrical signals carried by nerve cells also trigger the rapid release of the energy-mobilizing hormone adrenaline by ball-shaped neuroendocrine cells in the adrenal gland. The TAU investigators introduced Munc13-1 protein tagged with a green-fluorescent protein (GFP) into neuroendocrine cells to visualize the location of Munc13-1 protein during various stages of release (see Figure 3). These results suggest that Munc13-1 participates in neuronal plasticity by regulating the amount and time-course of neurotransmitter release.
Dr. Ashery's research team is now investigating other chemical pathways involved in synaptic modulation. They are also setting up experimental systems to study the role of synaptic proteins in neurodegenerative diseases such as Parkinson's disease, Huntington's disease and Alzheimer's disease (synaptic degeneration and dysfunction are the main cause of dementia in Alzheimer's disease). In collaboration with the laboratory of Prof. Daniel Michaelson of the TAU Department of Neurobiochemistry, Dr. Ashery's laboratory is trying to elucidate the contribution of several Alzheimer's-associated genes to the formation and maintenance of synapses. To that end, they are already culturing hippocampal neurons from "knockout" mice lacking these genes and checking how the lack of their associated proteins affects synapse formation and transmission.
