Thyroid hormone is required for the pruning of afferent type II spiral ganglion neurons in the mouse cochlea

Abstract

Afferent connections to the sensory inner and outer hair cells in the cochlea refine and functionally mature during the thyroid hormone (TH)- critical period of inner ear development that occurs perinatally in rodents. In this study, we investigated the effects of hypothyroidism on afferent type II innervation to outer hair cells (OHCs) using the Snell dwarf mouse (Pit1dw). Using a transgenic approach to specifically label type II spiral ganglion neurons, we found that a lack of TH causes persistence of excess type II SGN connections to the OHCs, as well as continued expression of the hair cell functional marker, otoferlin, in the OHCs beyond the maturation period. We also observed a concurrent delay in efferent attachment to the OHCs. Supplementing with TH during the early postnatal period from postnatal day (P) 3 to P4 reversed the defect in type II SGN pruning but did not alter otoferlin expression. Our results show that hypothyroidism causes a defect in the large-scale pruning of afferent type II spiral ganglion neurons in the cochlea, and a delay in efferent attachment and the maturation of otoferlin expression. Our data suggest that the state of maturation of hair cells, as determined by otoferlin expression, may not regulate the pruning of their afferent innervation.

Hair Cell Afferent Synapses: Function and Dysfunction

“…fibers (Barclay et al 2011;Sundaresan et al 2016), to reach the mature configuration with each fiber exclusively innervating between 5 and 30 OHCs (Barclay et al 2011;Zhang and Coate 2017). This period of refinement is consistent with the reduction in the number of OHC synaptic ribbons that occurs from around P3 to the onset of hearing (Huang et al 2012).…”

Deafness and loss of cochlear hair cells in the absence of thyroid hormone transporters Slc16a2 (Mct8) and Slc16a10 (Mct10)

“…Finally, we note that the complex auditory phenotype of dko mice may involve additional defects not in the sensory epithelium or lateral wall, as T3 also influences the spiral ganglion 26 , 50 and brainstem auditory nuclei 51 .…”

Neuronal cell adhesion molecule (NrCAM) is expressed by sensory cells in the cochlea and is necessary for proper cochlear innervation and sensory domain patterning during development

“…We next asked whether NrCAM is expressed in the cochlea at postnatal stages, when auditory neurons in the periphery form synapses and undergo pruning events just prior to the onset of hearing (Huang et al, ; Sundaresan et al, ). At P1 in mouse, the sensory epithelial cells in the cochlea have mostly differentiated, and immature presynaptic ribbon bodies are detectable in both IHCs and OHCs (Huang et al, ; Kelley, ).…”

“…Postnatal Nrcam-null Mice Show Altered Profiles of Presynaptic Ribbon Bodies (Afferents) and Vesicular Acetylcholine Transporter Immunostaining (Efferents) At P10 in mouse, hearing commences (Polley et al, 2013) and one can detect the approximate "mature" profile of afferent ribbon synapses (Huang et al, 2012) and cholinergic efferent synapses (Bergeron et al, 2005). Several days prior, the cochlear sensory domain undergoes a robust phase of synapse formation and pruning (Huang et al, 2012;Sundaresan et al, 2016). We suspected this process might involve the activity of NrCAM because postnatal Nrcam-null samples (P6-P8) appeared to have defects in ribbon synapse maturation (data not shown).…”