title: LKB1 Regulates Mitochondria-Dependent Presynaptic Calcium Clearance and Neurotransmitter Release Properties at Excitatory Synapses along Cortical Axons.
abstract: Individual synapses vary significantly in their neurotransmitter release properties, which underlie complex information processing in neural circuits. Presynaptic Ca2+ homeostasis plays a critical role in specifying neurotransmitter release properties, but the mechanisms regulating synapse-specific Ca2+ homeostasis in the mammalian brain are still poorly understood. Using electrophysiology and genetically encoded Ca2+ sensors targeted to the mitochondrial matrix or to presynaptic boutons of cortical pyramidal neurons, we demonstrate that the presence or absence of mitochondria at presynaptic boutons dictates neurotransmitter release properties through Mitochondrial Calcium Uniporter (MCU)-dependent Ca2+ clearance. We demonstrate that the serine/threonine kinase LKB1 regulates MCU expression, mitochondria-dependent Ca2+ clearance, and thereby, presynaptic release properties. Re-establishment of MCU-dependent mitochondrial Ca2+ uptake at glutamatergic synapses rescues the altered neurotransmitter release properties characterizing LKB1-null cortical axons. Our results provide novel insights into the cellular and molecular mechanisms whereby mitochondria control neurotransmitter release properties in a bouton-specific way through presynaptic Ca2+ clearance.
authors.affiliation: Columbia University Medical Center, Department of Neuroscience, Mortimer B. Zuckerman Mind Brain Behavior Institute, Kavli Institute for Brain Science, New York, New York, United States of America.
authors.forename: Seok-Kyu
authors.initials: SK
authors.lastname: Kwon
authors.affiliation: The Scripps Research Institute, Dorris Neuroscience Center, La Jolla, California, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Sando
authors.affiliation: Columbia University Medical Center, Department of Neuroscience, Mortimer B. Zuckerman Mind Brain Behavior Institute, Kavli Institute for Brain Science, New York, New York, United States of America.
authors.forename: Tommy L
authors.identifier: 0000-0001-7033-7010
authors.initials: TL
authors.lastname: Lewis
authors.affiliation: Columbia University Medical Center, Department of Neuroscience, Mortimer B. Zuckerman Mind Brain Behavior Institute, Kavli Institute for Brain Science, New York, New York, United States of America.
authors.forename: Yusuke
authors.identifier: 0000-0003-3950-6781
authors.initials: Y
authors.lastname: Hirabayashi
authors.affiliation: The Scripps Research Institute, Dorris Neuroscience Center, La Jolla, California, United States of America.
authors.forename: Anton
authors.initials: A
authors.lastname: Maximov
authors.affiliation: Columbia University Medical Center, Department of Neuroscience, Mortimer B. Zuckerman Mind Brain Behavior Institute, Kavli Institute for Brain Science, New York, New York, United States of America.
authors.forename: Franck
authors.initials: F
authors.lastname: Polleux
mesh_terms: D055372:AMP-Activated Protein Kinases; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology; D015153:Blotting, Western; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D059008:Time-Lapse Imaging / Q000379:methods
chemical_list: D015220:Calcium Channels; D018377:Neurotransmitter Agents; C034703:mitochondrial calcium uniporter; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D002118:Calcium