title: Fragile X mental retardation protein knockdown in the developing Xenopus tadpole optic tectum results in enhanced feedforward inhibition and behavioral deficits.
abstract: Fragile X Syndrome is the leading monogenetic cause of autism and most common form of intellectual disability. Previous studies have implicated changes in dendritic spine architecture as the primary result of loss of Fragile X Mental Retardation Protein (FMRP), but recent work has shown that neural proliferation is decreased and cell death is increased with either loss of FMRP or overexpression of FMRP. The purpose of this study was to investigate the effects of loss of FMRP on behavior and cellular activity.
  
  
  
  We knocked down FMRP expression using morpholino oligos in the optic tectum of Xenopus laevis tadpoles and performed a series of behavioral and electrophysiological assays. We investigated visually guided collision avoidance, schooling, and seizure propensity. Using single cell electrophysiology, we assessed intrinsic excitability and synaptic connectivity of tectal neurons.
  
  
  
  We found that FMRP knockdown results in decreased swimming speed, reduced schooling behavior and decreased seizure severity. In single cells, we found increased inhibition relative to excitation in response to sensory input.
  
  
  
  Our results indicate that the electrophysiological development of single cells in the absence of FMRP is largely unaffected despite the large neural proliferation defect. The changes in behavior are consistent with an increase in inhibition, which could be due to either changes in cell number or altered inhibitory drive, and indicate that FMRP can play a significant role in neural development much earlier than previously thought.
authors: Department of Neuroscience, Brown University, Box G-LN, 60 Olive St., 02912, Providence, RI, USA.
authors: Torrey L S
authors: TL
authors: Truszkowski
authors: Department of Neuroscience, Brown University, Box G-LN, 60 Olive St., 02912, Providence, RI, USA.
authors: Eric J
authors: EJ
authors: James
authors: Department of Neuroscience, Brown University, Box G-LN, 60 Olive St., 02912, Providence, RI, USA.
authors: Mashfiq
authors: M
authors: Hasan
authors: Department of Molecular and Cellular Neuroscience, Scripps Research Institute, 10550 North Torrey Pines Road, 92037, La Jolla, CA, USA.
authors: Tyler J
authors: TJ
authors: Wishard
authors: Department of Zoology and Physiology, University of Wyoming, 82071, Laramie, WY, USA.
authors: Zhenyu
authors: Z
authors: Liu
authors: Department of Zoology and Physiology, University of Wyoming, 82071, Laramie, WY, USA.
authors: Kara G
authors: KG
authors: Pratt
authors: Department of Molecular and Cellular Neuroscience, Scripps Research Institute, 10550 North Torrey Pines Road, 92037, La Jolla, CA, USA.
authors: Hollis T
authors: HT
authors: Cline
authors: Department of Neuroscience, Brown University, Box G-LN, 60 Olive St., 02912, Providence, RI, USA. carlos_aizenman@brown.edu.
authors: Carlos D
authors: CD
authors: Aizenman
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004924:Escape Reaction / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D055785:Gene Knockdown Techniques; D008564:Membrane Potentials; D009433:Neural Inhibition; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D012640:Seizures / Q000235:genetics; D013477:Superior Colliculi / Q000378:metabolism / Q000502:physiology*; D013550:Swimming / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1
keywords: FMRP; Fragile X Mental Retardation Protein; Fragile X syndrome; Xenopus laevis; inhibition