title: Astrocytes refine cortical connectivity at dendritic spines.
abstract: During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: W Christopher
authors.initials: WC
authors.lastname: Risher
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Sagar
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Il Hwan
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uezu
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, United States.
authors.forename: Srishti
authors.initials: S
authors.lastname: Bhagat
authors.affiliation: Department of Neurology, FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Wilton
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, United States.
authors.forename: Louis-Jan
authors.initials: LJ
authors.lastname: Pilaz
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Jonnathan
authors.initials: J
authors.lastname: Singh Alvarado
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Osman Y
authors.initials: OY
authors.lastname: Calhan
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Silver
authors.affiliation: Department of Neurology, FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Calakos
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Soderling
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Cagla
authors.initials: C
authors.lastname: Eroglu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D013569:Synapses / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C503127:Sparcl1 protein, mouse
keywords: astrocytes; cell biology; dendritic spines; mouse; neuroscience; synaptogenesis; thalamocortical