| NAWEED I. SYED Professor and
Head PUBMED: click here Institute
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In my research, I utilize modern, state-of-the-art electrophysiological, patchclamp, time-lapse video and fluorescence imaging, cell culture and molecular biological techniques to elucidate cellular, synaptic and molecular mechanisms of rhythmogenesis and synaptogenesis in a wide variety of vertebrate and invertebrate species. My prime interest is in the cellular and molecular basis of rhythm generation and specific synapse formation. I specifically study the intrinsic and network properties of various neuronal ensembles which underlie rhythmic behaviors between the identified Lymnaea neurons such as locomotion and respiration. I am also interested in investigating the cellular and molecular mechanisms underlying nervous system development and plasticity. My research program is directed towards determining how neurons find their path en route towards their targets and form specific synaptic connections with other neurons, and how their morphology and physiology is modified by injury or environmental stress. Finding answers to these questions is fundamental if we are to fully understand nervous system functions.
First in vitro central pattern generator and first transplanted neuron to regenerate In my research, I utilize the large, individually identifiable neurons from various invertebrate species (e.g., the pond snails Helisoma and Lymnaea, Aplysia, Crab, etc.) and vertebrates neurons from fish and frog. These neurons can be examined both during development (i.e. in the embryo or hatching) and in the adult, and they have a remarkable capacity to regenerate when damaged. Thus many important aspects of neural development and regeneration (e.g. neurite outgrowth, growth cone motility, synapse formation) can be readily investigated. Such experiments offer several advantages over similar studies being done on mammalian neural tissues, especially with regard to the ease with which they can be undertaken. First, the snails are inexpensive to raise and their neurons are not only very amenable to experimentation (e.g. intracellular microelectrode recording) but can be identified as individuals with distinct morphological and physiological characteristics. Second, since developmental and regenerational studies can be carried out in the animal (in vivo), in organ culture, or in isolated cell culture (in vitro), one can examine a particular biological problem on several different levels - ranging from the behavioral to the molecular. During the course of my Ph.D., I characterized the respiratory behavior of the pond snail Lymnaea stagnalis and identified motor neurons and interneurons that comprise a central pattern generator (CPG). I then successfully reconstructed this respiratory CPG in vitro. Furthermore, I have also performed single cell transplants of the respiratory interneurons in the intact animals. These transplanted neurons not only exhibit neurite outgrowth but also restore the functional circuitry that underlies the respiratory behavior. At present, utilizing these in vitro and in vivo model systems, I am investigating the cellular and molecular mechanisms underlying target cell selection, specific synapse formation and growth cone collapse between identified motor neurons and interneurons. More recently, in collaboration with our colleagues at the Max Plank Institute, Germany, we have successfully interfaced neuronal chemical synapses with semiconductor chips. This approach now allows us to simultaneously monitor neuronal activity from a large ensemble of neuronal circuits. Moreover, these chips can now be transplanted in animals and humans to drive artificial prosthetic devices.
SIGNIFICANT RESEARCH 1. First successful attempt to reconstruct a pattern generator in vitro. This paper was accompanied by an editorial review entitled “High Culture of Neuroscience” in Science (1990; 250: 282-285). Similarly, the Medical Post (Toronto), CBC, CFCN, 2 and 7 News and Calgary Herald ran cover stories on the significance of this research. This work has been the focus of many text books and review articles and provides direct insights into the cellular and synaptic basis of rhythm generation. 2. First successful demonstration that a single transplanted neuron restores the deficit in the respiratory behavior by integrating into host circuitry. This work was published in Neuron. These studies have allowed us to test the involvement of individual neurons in the control of respiratory behavior, and also may help to develop techniques to perform successful brain cell transplants in the higher animals. [Syed et al.;1992, Neuron 8: 767-774 - with cover picture]. This work has also been the focus of many review articles and book chapters. 3. Identification and characterization of the first neurotrophic factor from an invertebrate species. [Fainzilber et al; 1996 Science 274: 1540-1543]. These studies are important because the identified Lymnaea trophic factor also bind to the vertebrate p75 receptor, suggesting that the mechanisms underlying neurotrophic receptor-induced neurite outgrowth may be common and fundamental to both vertebrates and invertebrates. 4. Utilizing soma-soma synapses between identified Lymnaea neurons, our laboratory has provided the first direct evidence that both inhibitory (Feng et al., 1997, J. Neuroscience 17 (20): 7839-7849, 1997) and excitatory synapse formation (Hamakawa et al, J. Neuroscience 19(21): 9306-9312 1999 and Woodin et al., 1999, Learning and Memory 6:307-316, -with cover picture) is differentially regulated by extrinsic trophic factors. These studies have extended the role of neurotrophic factors from neuronal survival, outgrowth to synapse formation and synaptic plasticity. We have provided the first direct evidence that the trophic factors-induced plasticity and specificity of excitatory synapse formation requires de novo protein synthesis, transcription and is mediated via receptor tyrosine kinases. Most importantly, these studies demonstrated that in the absence of specific trophic factors, not only do appropriate excitatory synapses fail to develop but that the neurons establish inappropriate inhibitory synapses which we have referred to as “default” synapses. The default synapses can however be corrected by the addition of appropriate trophic factors. These studies, taken together have allowed us to propose a novel concept in the field of neurodevelopment and synapse formation. 5. Identification and characterization of a novel glia-derived acetylcholine-binding protein that modulates synaptic transmission between cultured Lymnaea neuron. (Smit et al., 2001, Nature 411:261-268 - article accompanied by News Views 252-253). In this study, we have demonstrated that glial cells modulate cholinergic synaptic transmission between the paired cells. We subsequently identified a novel glial-derived soluble acetylcholine-binding protein (AchBP), which is a naturally occurring analogue of the ligand-binding domains of the nicotinic acetylcholine receptors (nAchRs). Like the AchRs, it assembles into a homopentamer with ligand-binding characteristics hat are typical for a nicotinic receptor. Unlike the nAchRs, however, it lacks the domains, which form a trans-membrane ion channel. Pre-synaptically released Ach induces the secretion of AchPB into the synaptic cleft through the glial secretory pathway, where it regulates cholinergic transmission between neurons. My contributions to this study were 40%. The experimental model used in this study was developed (soma-soma/glia) by myself. Similarly, all experiments testing the functional significance of AchBP were performed by myself. I was also responsible for the experimental design, manuscript structure and its writeup.
Growth cones CURRENT
RESEARCH SUPPORT ADMINISTRATIVE SUPPORT Carolyn Taylor Wali Zaidi -
Technician GRADUATE
STUDENTS POSTDOCTORAL
FELLOWS
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