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Morgan Sheng
A single synapse is thought to comprise hundreds of distinct proteins. The goal of Professor Morgan Sheng's lab: to identify and understand all of these proteins, particularly those critical to the work of creating memories. The lab's progress in decoding the synaptic architecture may lead to a deeper understanding of how synaptic connections may go wrong in disorders such as Alzheimer's, schizophrenia and autism.
The brain is a massive network of electrically active cells (neurons) that communicate with each other via specialized cell junctions (synapses). Throughout development and in adult life, the brain responds to experience by adjusting the strength of communication at individual synapses and by changing the physical pattern of synaptic connections between neurons. In this way, information can be stored by the nervous system in the form of altered structure and chemistry of synapses, and/or by the formation of new synapses and the elimination of old ones. This so-called "plasticity" of synapses is believed to be the basis of learning and memory in the brain.
Because of their central importance in information processing and storage, it is important to understand the molecular architecture of synapses and the cellular processes that govern synapse formation, growth and elimination. By using biochemical, genetic and imaging approaches to study the dynamic organization of synapses, we hope to reveal the fundamental molecular mechanisms by which the brain modifies itself and adapts to experience. Moreover, because synaptic function often goes awry in neurological and psychiatric disorders, our research should shed light on the molecular and genetic causes of brain and mental disease.
Taking a "bottoms-up" approach, we are systematically characterizing the individual protein components of synapses and elucidating how these proteins interact with each other to make up the synaptic junction. Synapses consist of a presynaptic neuron that releases a chemical messenger (neurotransmitter) across a narrow gap to stimulate the postsynaptic neuron. Our focus is on the postsynaptic side of excitatory synapses, which use glutamate as the neurotransmitter. Attached to the postsynaptic membrane is a specialized microscopic structure called the postsynaptic density (PSD). The PSD contains the receptors for the neurotransmitter glutamate (glutamate receptors), of which there are three major classes: NMDA receptors, AMPA receptors, and metabotropic glutamate receptors. In addition, there are several hundred "supporting" proteins in the PSD that are involved in localizing the receptors at the synapse and that mediate signaling processes activated by the receptors. By activation of distinct postsynaptic signaling pathways, different patterns of synaptic stimulation can lead to either strengthening or weakening of synaptic transmission. The details of these synaptic signaling mechanisms, and how they cause changes in the structure and strength of synapses, are being worked out.
What are the specific functions of the individual protein components of the PSD? We are taking several approaches to address this question for the key PSD proteins. First, we can overexpress the protein in cells or in the brain and see what it does to neuronal morphology, synapse development and synaptic function. Second, we can devise mutant variants of the protein (so called "dominant negative" mutants) that when introduced into cells should impair the activity of the endogenous normal protein. Thirdly, we can specifically get rid of the protein in neurons by so-called "RNA interference." Finally, we can disrupt the gene in the animal (mouse) by genetic engineering and create a mutant mouse lacking the specific protein. In the last case, we can evaluate how the gene contributes to behavior and cognitive function (for instance, how the mutant mouse performs in learning and memory tasks).
Using such approaches, we are investigating the function of the key components of the PSD in the regulation of dendritic spines, which are tiny protrusions found on the branches of many neurons. Dendritic spines are specialized morphological compartments on which excitatory synapses are formed, and these fascinating structures change in size and shape depending on a wide variety of factors such as brain activity, neurological disease, hormonal cycles and aging. It is believed that changes in dendritic spine number and morphology reflect synaptic plasticity, particularly changes in synaptic connections between neurons. As an example of our work, we have found that a protein of the PSD called Shank links together NMDA receptor and metabotropic glutamate receptor complexes with the actin cytoskeleton and is important for the growth and maturation of dendritic spines. A mutant mouse that is deficient for Shank appears outwardly normal, but shows profound behavioral abnormalities and cognitive deficits.
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