Glutamate receptor recruitment to new synapses in vivo

Summary

Principal Investigator: PHILIP ERIC WASHBOURNE
Affiliation: University of Oregon
Country: USA
Abstract: Chemical synapses are the primary means for transmitting information from one neuron to the next. Synapses are initially formed during development of the nervous system, and formation of appropriate synapses is crucial for establishment of neuronal circuits that underlie behavior and cognition. Minor irregularities during synapse formation can lead to developmental disorders such as autism, mental retardation and may contribute to psychological disorders. Most synapses in the vertebrate central nervous system (CNS) depend on the neurotransmitter glutamate, and thus glutamatergic synapses have been an important focus of study in trying to unravel these and other neurological disorders. A novel family of cell adhesion molecules (CAMs), the Synaptic Cell Adhesion Molecules (SynCAMs), has recently been proposed to mediate the formation of synapses. However, this work is based on experiments in neuronal culture, and knock-out mouse data so far does not corroborate this. Furthermore, it remains unknown how the SynCAMs, and CAMs in general, bring about the recruitment of synaptic elements to new adhesive contacts. We propose to test a model describing specific mechanisms through which SynCAM family members 1 and 2 can recruit both synaptic vesicles (SVs) to the presynaptic terminal and glutamate receptors to the postsynaptic specialization. We hypothesize that an interaction between SynCAM1 or 2 and CASK in axons can directly tether SV precursors to the site of SynCAM/SynCAM interaction. We also propose that binding of DAL-1 to SynCAM1 or 2 in dendrites results in formation of an actin/spectrin subsynaptic scaffold. These cytoskeletal elements then serve two functions: 1) strengthening of the adhesive nature of the synapse and morphological remodeling to generate a spine and 2) recruitment of NMDA type glutamate receptor transport packets via an actin-dependent transport mechanism. We propose to use a variety of techniques including biochemistry, immunolabeling, live-imaging, electrophysiology and behavioral tests, because a multidisciplinary approach will comprehensively test our model. We also propose to use various neuronal preparations for our experiments including cultured hippocampal neurons, cultured cerebellar granule cells (CGCs) and spinal cord neurons in zebrafish embryos in vivo. Testing our hypothesis in zebrafish will shed light on whether these proteins and their interactions are required for forming a specific circuit in a developing embryo that is required for a sensorimotor reflex. Our approach gives us the unprecedented opportunity to determine the mechanisms of glutamatergic synapse formation using behavioral, electrophysiological, genetic and biochemical approaches in both neuronal cultures and in a living vertebrate. PUBLIC HEALTH RELEVANCE: Synapses are sites at which nerve cells communicate with each other. Communication of nerve cells is absolutely necessary for nervous system function, ranging from simple reflexes to expressing philosophical thoughts. Errors during the formation of synapses are thought to be at the basis of nervous system disorders such as autism, mental retardation and schizophrenia. We propose to study two members of a family of genes, the Synaptic Cell Adhesion Molecules (SynCAMs) 1 and 2, which are thought to mediate the formation of synapses during development. Almost nothing is yet known about how SynCAMs make a contact site between two nerve cells become a place for active communication. We will investigate how these molecules carry out synapse formation by testing their function in rat nerve cells grown in culture and by testing their function in developing zebrafish embryos. These two systems allow us to determine the nature of the molecular interactions and to determine the importance of these interactions for the formation of synapses in a living organism, respectively. Our research will help understand the mechanisms by which synapses form and bring us closer to identifying the molecular deficits in individuals with autism and mental retardation.
Funding Period: ----------------2009 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Six cadm/SynCAM genes are expressed in the nervous system of developing zebrafish
    Thomas Pietri
    Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA
    Dev Dyn 237:233-46. 2008
  2. pmc Neuroligin1 drives synaptic and behavioral maturation through intracellular interactions
    Jennifer L Hoy
    Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA
    J Neurosci 33:9364-84. 2013
  3. pmc Late recruitment of synapsin to nascent synapses is regulated by Cdk5
    Courtney Easley-Neal
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Cell Rep 3:1199-212. 2013
  4. pmc The first mecp2-null zebrafish model shows altered motor behaviors
    Thomas Pietri
    Ecole Normale Superieure, Institut de Biologie de l ENS Paris, France INSERM, U1024 Paris, France CNRS, UMR 8197 Paris, France
    Front Neural Circuits 7:118. 2013
  5. doi Organization of central synapses by adhesion molecules
    Alexandra Tallafuss
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Eur J Neurosci 32:198-206. 2010
  6. pmc Differential expression of neuroligin genes in the nervous system of zebrafish
    Crystal Davey
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, USA
    Dev Dyn 239:703-14. 2010
  7. pmc Turning gene function ON and OFF using sense and antisense photo-morpholinos in zebrafish
    Alexandra Tallafuss
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Development 139:1691-9. 2012
  8. pmc SynCAM1 recruits NMDA receptors via protein 4.1B
    Jennifer L Hoy
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Mol Cell Neurosci 42:466-83. 2009
  9. pmc Glutamate drives the touch response through a rostral loop in the spinal cord of zebrafish embryos
    Thomas Pietri
    Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA
    Dev Neurobiol 69:780-95. 2009
  10. pmc Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy
    Gavin J Wright
    Wellcome Trust Sanger Institute, Cambridge, UK
    J Neurochem 117:765-78. 2011

Scientific Experts

  • Alexandra Tallafuss
  • Philip Washbourne
  • Thomas Pietri
  • Jennifer L Hoy
  • Courtney Easley-Neal
  • Gavin J Wright
  • Crystal Davey
  • Renee J Arias
  • Michael Wehr
  • Raluca McCallum
  • Paola A Haeger
  • Lawrence Davis
  • German Sumbre
  • Michael Kyweriga
  • JoAnn Buchanan
  • Cecilia B Moens
  • Nicolas Guyon
  • Angel Carlos Roman
  • Gonzalo G de Polavieja
  • Javier Fierro
  • Eric Schnell
  • John R L Constable
  • Sebastian A Romano
  • Pablo E Castillo
  • Louis Saint-Amant
  • Zhanyan Fu
  • John R Constable
  • Elise Manalo
  • Joel Ryan
  • Stefano Vicini
  • Catherine Wilson

Detail Information

Publications10

  1. pmc Six cadm/SynCAM genes are expressed in the nervous system of developing zebrafish
    Thomas Pietri
    Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA
    Dev Dyn 237:233-46. 2008
    ..All six zebrafish cadms are expressed throughout the nervous system both during development and in the adult. The spatial and temporal patterns of expression suggest multiple roles for Cadms during nervous system development...
  2. pmc Neuroligin1 drives synaptic and behavioral maturation through intracellular interactions
    Jennifer L Hoy
    Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA
    J Neurosci 33:9364-84. 2013
    ..This has significant implications for our ability to address disorders such as autism spectrum disorders...
  3. pmc Late recruitment of synapsin to nascent synapses is regulated by Cdk5
    Courtney Easley-Neal
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Cell Rep 3:1199-212. 2013
    ..Importantly, cyclin-dependent kinase 5 (Cdk5) specifically regulated the late recruitment of synapsin transport packets at synapses. These results point to additional layers of complexity in the established mechanisms of synaptogenesis...
  4. pmc The first mecp2-null zebrafish model shows altered motor behaviors
    Thomas Pietri
    Ecole Normale Superieure, Institut de Biologie de l ENS Paris, France INSERM, U1024 Paris, France CNRS, UMR 8197 Paris, France
    Front Neural Circuits 7:118. 2013
    ..They present nonetheless clear behavioral alterations during their early development, including spontaneous and sensory-evoked motor anomalies, as well as defective thigmotaxis. ..
  5. doi Organization of central synapses by adhesion molecules
    Alexandra Tallafuss
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Eur J Neurosci 32:198-206. 2010
    ..Here we focus on recent reports describing how synaptic cell adhesion molecules interact with and organize the presynaptic and postsynaptic specializations of both excitatory and inhibitory central synapses...
  6. pmc Differential expression of neuroligin genes in the nervous system of zebrafish
    Crystal Davey
    Institute of Neuroscience, University of Oregon, Eugene, Oregon, USA
    Dev Dyn 239:703-14. 2010
    ..The spatial and temporal expression patterns of these genes suggest that they occupy a role in nervous system development and maintenance...
  7. pmc Turning gene function ON and OFF using sense and antisense photo-morpholinos in zebrafish
    Alexandra Tallafuss
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Development 139:1691-9. 2012
    ..Our results suggest that sox10 function might not be critical during neural crest formation...
  8. pmc SynCAM1 recruits NMDA receptors via protein 4.1B
    Jennifer L Hoy
    Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
    Mol Cell Neurosci 42:466-83. 2009
    ..1N to specifically effect AMPA type receptor (AMPAR) recruitment. Thus, SynCAM1 may recruit both AMPARs and NMDARs by independent mechanisms during synapse formation...
  9. pmc Glutamate drives the touch response through a rostral loop in the spinal cord of zebrafish embryos
    Thomas Pietri
    Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, USA
    Dev Neurobiol 69:780-95. 2009
    ..This helps define an elementary circuit that is modified by the addition of sensory inputs, resulting in behavioral transformation...
  10. pmc Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy
    Gavin J Wright
    Wellcome Trust Sanger Institute, Cambridge, UK
    J Neurochem 117:765-78. 2011
    ..Furthermore, the capability of performing high-throughput drug screens suggests that these small vertebrates may prove extremely useful in identifying pharmacological approaches to treating autism spectrum disorders...