title: Neural Activity-Dependent Regulation of Radial Glial Filopodial Motility Is Mediated by Glial cGMP-Dependent Protein Kinase 1 and Contributes to Synapse Maturation in the Developing Visual System.
abstract: Radial glia in the developing optic tectum extend highly dynamic filopodial protrusions within the tectal neuropil, the motility of which has previously been shown to be sensitive to neural activity and nitric oxide (NO) release. Using in vivo two-photon microscopy, we performed time-lapse imaging of radial glial cells and measured filopodial motility in the intact albino Xenopus laevis tadpole. Application of MK801 to block neuronal NMDA receptor (NMDAR) currents confirmed a significant reduction in radial glial filopodial motility. This reduction did not occur in glial cells expressing a dominant-negative form of cGMP-dependent protein kinase 1 (PKG1), and was prevented by elevation of cGMP levels with the phosphodiesterase type 5 inhibitor sildenafil. These results suggest that neuronal NMDAR activation results in the release of NO, which in turn modulates PKG1 activation in glial cells to control filopodial motility. We further showed that interfering with the function of the small GTPases Rac1 or RhoA, known to be regulated by PKG1 phosphorylation, decreased motility or eliminated filopodial processes respectively. These manipulations led to profound defects in excitatory synaptic development and maturation of neighboring neurons.
  
  
  
  Radial glia in the developing brain extend motile filopodia from their primary stalk. Neuronal NMDA receptor activity controls glial motility through intercellular activation of cGMP-dependent protein kinase 1 (PKG1) signaling in glial cells. Manipulating PKG1, Rac1, or RhoA signaling in radial glia in vivo to eliminate glial filopodia or impair glial motility profoundly impacted synaptogenesis and circuit maturation.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and Department of Psychiatry, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Mari
authors.identifier: 0000-0003-2262-1572
authors.initials: M
authors.lastname: Sild
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and.
authors.forename: Marion R
authors.initials: MR
authors.lastname: Van Horn
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and.
authors.forename: Anne
authors.initials: A
authors.lastname: Schohl
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and.
authors.forename: Dantong
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute and edward.ruthazer@mcgill.ca.
authors.forename: Edward S
authors.identifier: 0000-0003-0452-3151
authors.initials: ES
authors.lastname: Ruthazer
mesh_terms: D000818:Animals; D002465:Cell Movement; D006152:Cyclic GMP / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D011554:Pseudopodia / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D000068677:Sildenafil Citrate / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism; D014795:Visual Pathways / Q000254:growth & development* / Q000378:metabolism; D014982:Xenopus laevis; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D000068677:Sildenafil Citrate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D006152:Cyclic GMP
keywords: NMDA receptor; PKG; astrocyte; neuron–glia interaction; radial glia; retinotectal; synaptogenesis