title: Thyroid hormone is required for pruning, functioning and long-term maintenance of afferent inner hair cell synapses.
abstract: Functional maturation of afferent synaptic connections to inner hair cells (IHCs) involves pruning of excess synapses formed during development, as well as the strengthening and survival of the retained synapses. These events take place during the thyroid hormone (TH)-critical period of cochlear development, which is in the perinatal period for mice and in the third trimester for humans. Here, we used the hypothyroid Snell dwarf mouse (Pit1(dw)) as a model to study the role of TH in afferent type I synaptic refinement and functional maturation. We observed defects in afferent synaptic pruning and delays in calcium channel clustering in the IHCs of Pit1(dw) mice. Nevertheless, calcium currents and capacitance reached near normal levels in Pit1(dw) IHCs by the age of onset of hearing, despite the excess number of retained synapses. We restored normal synaptic pruning in Pit1(dw) IHCs by supplementing with TH from postnatal day (P)3 to P8, establishing this window as being critical for TH action on this process. Afferent terminals of older Pit1(dw) IHCs showed evidence of excitotoxic damage accompanied by a concomitant reduction in the levels of the glial glutamate transporter, GLAST. Our results indicate that a lack of TH during a critical period of inner ear development causes defects in pruning and long-term homeostatic maintenance of afferent synapses.
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Stanford University, 300 Pasteur Drive, Room R111A, Stanford, CA, 94035, USA.
authors.forename: Srividya
authors.initials: S
authors.lastname: Sundaresan
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Stanford University, 300 Pasteur Drive, Room R111A, Stanford, CA, 94035, USA.
authors.forename: Jee-Hyun
authors.initials: JH
authors.lastname: Kong
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Stanford University, 300 Pasteur Drive, Room R111A, Stanford, CA, 94035, USA.
authors.forename: Felipe T
authors.initials: FT
authors.lastname: Salles
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Stanford University, 300 Pasteur Drive, Room R111A, Stanford, CA, 94035, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Wangsawihardja
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Stanford University, 300 Pasteur Drive, Room R111A, Stanford, CA, 94035, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Ricci
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Stanford University, 300 Pasteur Drive, Room R111A, Stanford, CA, 94035, USA.
authors.forename: Mirna
authors.initials: M
authors.lastname: Mustapha
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D056970:Co-Repressor Proteins; D003051:Cochlea / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D050817:Transcription Factor Pit-1 / Q000235:genetics; D014284:Triiodothyronine / Q000008:administration & dosage / Q000502:physiology*
chemical_list: D000429:Alcohol Oxidoreductases; D020746:Calcium Channels, L-Type; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D027341:Excitatory Amino Acid Transporter 1; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D050817:Transcription Factor Pit-1; D014284:Triiodothyronine; C485995:Cacna1d protein, mouse; C494185:Pou1f1 protein, mouse; C512412:SHANK1 protein, mouse; C493393:Slc1a3 protein, mouse; C111341:Ctbp2 protein, mouse
keywords: auditory system; calcium current; capacitance measurements; glutamate transporter