Area:
Neurobiology of Learning and Memory, Synapses and Circuits, Axon Pathfinding and Synaptogenesis, Cellular/Molecular/Developmental Neuroscience
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High-probability grants
According to our matching algorithm, Samuel M. Schacher is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2002 — 2009 |
Schacher, Samuel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Formation of Specific Synapses @ Columbia University Health Sciences
Central neurons form and maintain specific connections, which are critical for the proper functioning of the nervous system. In Aplysia many central neurons are identified functionally because of their specific connections with central or peripheral targets. Aplysia sensory neurons in cell culture form specific synapses (with motor neuron L7 but not L11) even when they interact with both targets simultaneously. How do neurons establish specific synapses when interacting simultaneously with appropriate and inappropriate partners? Target-induced local secretion of a neuropeptide, sensorin, from sensory neurons and its autocrine signaling regulate presynaptic axonal growth associatedwith the formation and maintenance of specific sensory neuron synapses. Sensorin and its signaling pathway also regulate the distribution and expression of its own mRNA and protein and that of other mRNAs that encode proteins critical for synaptic function. Both sensorin mRNA and mRNAs for some of the proteins critical for synaptic function are also transported to terminals, and target-dependent regulation of mRNA localization and local translation contribute to the formation of sensory neuron synapses. Thus a retrograde signal from a specific postsynaptic target neuron regulates the expression, secretion and signaling of a presynaptic neuropeptide, which in turn regulates a number of cellular processes required for synapse-associated growth and the formation of specific synapses. Using cellular methods (electrophysiology, pharmacology, immunostaining and light microscopy) and molecular techniques (RT-PCR, in situ hybridization, anti-sense knock down methods, and expression of GFP-tagged constructs), we plan to use a model cell culture system containing identified neurons of the marine mollusk Aplysia to test the above hypothesis by examining the following aims: 1) To determine how the appropriate target regulates the expression and secretion of the neuropeptide. 2) To determine the signaling pathways that contribute to the formation of specific synapses. 3) To determine how the neuropeptide regulates cellular processes in both presynaptic neuron and target that are associated with the formation of synapses. The results will provide fundamental understanding into the normal cellular processes that allow the proper development of neural circuits that regulate behavior. Failure to establish specific synaptic connections during development may contribute to several disorders of nervous system function expressed either during early life or only after maturation.
|
0.915 |
2005 — 2007 |
Schacher, Samuel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Protein Kinase C Controls Synaptic Action &Behavior @ Columbia University Health Sciences
DESCRIPTION (provided by applicant): Gene expression is thought to be the molecular basis of long term synaptic plasticity. Identified sensory neurons mediate well-characterized defensive reflexes in Aplysia. Plasticity of sensory-to-motor synapses underlies both sensitization and habituation of these reflexes. Much work has elucidated the cell- and molecular mechanisms underlying long term sensitization. A facilitatory neurotransmitter, eg serotonin, activates the cAMP-dependent protein kinase, which then is imported into the sensory neuron's nucleus to initiate a cascade of gene expression by phosphorylating the constitutive transcription activator, CREB1. The proteins synthesized are the structural basis for the enhanced transmitter release (facilitation) that underlies the alteration of behavior. We now plan to examine the molecular basis of long term depression (LTD), the physiological process underlying habituation. We showed that short term depression, which lasts for minutes, is produced by brief application of the inhibitory neuropeptide transmitter, FMRFamide; prolonged application results in LTD lasting days or weeks. The decrease in excitatory post-synaptic potentials that characterize synaptic depression is produced by an incompletely analyzed second-message pathway that involves receptor-mediated release of arachidonic acid, which is then converted to active metabolites by 12-lipoxygenase. We now find that the stress MAP kinase, p38, is activated by FMRFa during LTD, as has been reported for depression in pyramidal cells in the vertebrate hippocampus. Once activated, the kinase is imported into the sensory neuron's nucleus. We propose to characterize the signal transduction mechanisms by which p38 kinase operates, both in nucleus and cytoplasm. Since activation of transcription factors is known to induce the synthesis of the proteins needed for the maintenance and consolidation of synaptic plasticity, it is likely that p38 phosphorylates transcription factors. We therefore would identify those factors in order to determine what role p38 kinase plays in producing LTD. Finally we will identify the induced proteins that are required for LTD by differential screening. The mechanisms underlying synaptic plasticity are important because they are likely to be disturbed in mental disorders (schizophrenia and depression), and to play a crucial role in drug addiction. Aplysia neurons offer a convenient experimental system for approaching these processes successfully.
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0.915 |