title: Maintenance of neuronal size gradient in MNTB requires sound-evoked activity.
abstract: The medial nucleus of the trapezoid body (MNTB) is an important source of inhibition during the computation of sound location. It transmits fast and precisely timed action potentials at high frequencies; this requires an efficient calcium clearance mechanism, in which plasma membrane calcium ATPase 2 (PMCA2) is a key component. Deafwaddler (dfw2J) mutant mice have a null mutation in PMCA2 causing deafness in homozygotes (dfw2J/dfw2J) and high-frequency hearing loss in heterozygotes (+/dfw2J). Despite the deafness phenotype, no significant differences in MNTB volume or cell number were observed indfw2Jhomozygous mutants, suggesting that PMCA2 is not required for MNTB neuron survival. The MNTB tonotopic axis encodes high to low sound frequencies across the medial to lateral dimension. We discovered a cell size gradient along this axis: lateral neuronal somata are significantly larger than medially located somata. This size gradient is decreased in +/dfw2Jand absent indfw2J/dfw2JThe lack of acoustically driven input suggests that sound-evoked activity is required for maintenance of the cell size gradient. This hypothesis was corroborated by selective elimination of auditory hair cell activity with either hair cell elimination in Pou4f3 DTR mice or inner ear tetrodotoxin (TTX) treatment. The change in soma size was reversible and recovered within 7 days of TTX treatment, suggesting that regulation of the gradient is dependent on synaptic activity and that these changes are plastic rather than permanent.NEW & NOTEWORTHYNeurons of the medial nucleus of the trapezoid body (MNTB) act as fast-spiking inhibitory interneurons within the auditory brain stem. The MNTB is topographically organized, with low sound frequencies encoded laterally and high frequencies medially. We discovered a cell size gradient along this axis: lateral neurons are larger than medial neurons. The absence of this gradient in deaf mice lacking plasma membrane calcium ATPase 2 suggests an activity-dependent, calcium-mediated mechanism that controls neuronal soma size.
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, and Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington.|Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, and Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Weatherstone
authors.affiliation: Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom; cks@bio.lmu.de.|Division of Neurobiology, Department Biology II, Ludwig-Maximilians University Munich, Planegg-Martinsried, Germany.
authors.forename: Conny
authors.initials: C
authors.lastname: Kopp-Scheinpflug
authors.affiliation: Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom.|Autifony Srl Laboratories, Medicines Research Centre, Verona, Italy; and.
authors.forename: Nadia
authors.initials: N
authors.lastname: Pilati
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, and Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington.|Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Forsythe
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, and Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Rubel
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, and Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington.|Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, and Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Tempel
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D017626:Cochlear Nucleus / Q000473:pathology*; D003638:Deafness / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D004167:Diphtheria Toxin / Q000494:pharmacology; D005072:Evoked Potentials, Auditory / Q000235:genetics / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013016:Sound; D013779:Tetrodotoxin / Q000494:pharmacology; D050821:Transcription Factor Brn-3C / Q000235:genetics / Q000378:metabolism
chemical_list: D004167:Diphtheria Toxin; D018691:Excitatory Amino Acid Antagonists; D018398:Homeodomain Proteins; D008869:Microtubule-Associated Proteins; C121290:Pou4f3 protein, mouse; D026941:Sodium Channel Blockers; D050821:Transcription Factor Brn-3C; D013779:Tetrodotoxin; D015763:2-Amino-5-phosphonovalerate; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse
keywords: PMCA2; auditory brain stem; calyx of Held; synaptic transmission; tonotopic gradients