title: Defects in Motoneuron-Astrocyte Interactions in Spinal Muscular Atrophy.
abstract: Spinal muscular atrophy (SMA) is a motoneuron disease caused by loss or mutation in Survival of Motor Neuron 1 (SMN1) gene. Recent studies have shown that selective restoration of SMN protein in astrocytes partially alleviates pathology in an SMA mouse model, suggesting important roles for astrocytes in SMA. Addressing these underlying mechanisms may provide new therapeutic avenues to fight SMA. Using primary cultures of pure motoneurons or astrocytes from SMNΔ7 (SMA) and wild-type (WT) mice, as well as their mixed and matched cocultures, we characterized the contributions of motoneurons, astrocytes, and their interactions to synapse loss in SMA. In pure motoneuron cultures, SMA motoneurons exhibited normal survival but intrinsic defects in synapse formation and synaptic transmission. In pure astrocyte cultures, SMA astrocytes exhibited defects in calcium homeostasis. In motoneuron-astrocyte contact cocultures, synapse formation and synaptic transmission were significantly reduced when either motoneurons, astrocytes or both were from SMA mice compared with those in WT motoneurons cocultured with WT astrocytes. The reduced synaptic activity is unlikely due to changes in motoneuron excitability. This disruption in synapse formation and synaptic transmission by SMN deficiency was not detected in motoneuron-astrocyte noncontact cocultures. Additionally, we observed a downregulation of Ephrin B2 in SMA astrocytes. These findings suggest that there are both cell autonomous and non-cell-autonomous defects in SMA motoneurons and astrocytes. Defects in contact interactions between SMA motoneurons and astrocytes impair synaptogenesis seen in SMA pathology, possibly due to the disruption of the Ephrin B2 pathway.
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-2520.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-2520.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-2520 cko@usc.edu.
authors.forename: Chien-Ping
authors.identifier: http://orcid.org/0000-0002-3365-0005
authors.initials: CP
authors.lastname: Ko
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000473:pathology
keywords: astrocytes; ephrin B2; motoneurons; spinal muscular atrophy; synapses; synaptic transmission