title: Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout Mice.
abstract: Altered neuronal excitability is one of the hallmarks of fragile X syndrome (FXS), but the mechanisms underlying this critical neuronal dysfunction are poorly understood. Here, we find that pyramidal cells in the entorhinal cortex of Fmr1 KO mice, an established FXS mouse model, display a decreased AP threshold and increased neuronal excitability. The AP threshold changes in Fmr1 KO mice are caused by increased persistent sodium current (INaP). Our results indicate that this abnormal INaP in Fmr1 KO animals is mediated by increased mGluR5-PLC-PKC (metabotropic glutamate receptor 5/phospholipase C/protein kinase C) signaling. These findings identify Na(+) channel dysregulation as a major cause of neuronal hyperexcitability in cortical FXS neurons and uncover a mechanism by which abnormal mGluR5 signaling causes neuronal hyperexcitability in a FXS mouse model.
authors.affiliation: Departments of Cell Biology and Physiology, Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Pan-Yue
authors.initials: PY
authors.lastname: Deng
authors.affiliation: Departments of Cell Biology and Physiology, Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: klyachko@wustl.edu.
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Klyachko
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D018728:Entorhinal Cortex / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse