title: FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.
abstract: Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel's regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology.
authors: Departments of Biomedical Engineering and Cell Biology and Physiology, CIMED, Washington University, St. Louis, MO 63110, USA.
authors: Pan-Yue
authors: PY
authors: Deng
authors: Ziv
authors: Z
authors: Rotman
authors: Jay A
authors: JA
authors: Blundon
authors: Yongcheol
authors: Y
authors: Cho
authors: Jianmin
authors: J
authors: Cui
authors: Valeria
authors: V
authors: Cavalli
authors: Stanislav S
authors: SS
authors: Zakharenko
authors: Vitaly A
authors: VA
authors: Klyachko
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D017729:Presynaptic Terminals; D009435:Synaptic Transmission
chemical_list: D002118:Calcium; D051860:Fragile X Messenger Ribonucleoprotein 1; D051036:Large-Conductance Calcium-Activated Potassium Channels; D018377:Neurotransmitter Agents; C497684:Fmr1 protein, mouse