Maturation of Ribbon Synapses in Hair Cells Is Driven by Thyroid Hormone

Abstract

Ribbon synapses of inner hair cells (IHCsϪ/Ϫ mice maintained the normally temporary efferent innervation. Moreover, they lacked large-conductance Ca 2ϩ -activated K ϩ channels and KCNQ4 channels. This together with the persistently increased Ca 2ϩ influx permitted continued action potential generation. We conclude that TH regulates IHC differentiation and is essential for morphological and functional maturation of their ribbon synapses. We suggest that presynaptic dysfunction of IHCs is a mechanism in congenital hypothyroid deafness.

Thyroid Hormone Deficiency Affects Postnatal Spiking Activity and Expression of Ca2+and K+Channels in Rodent Inner Hair Cells

“…This dif- ference was caused by the lack of I K,f expression in Pax8 Ϫ/Ϫ IHCs at P12 or later, as confirmed by analysis of K ϩ current activation time constants and immunohistochemistry (data not shown) (Sendin et al, 2007), similar to our findings for IHCs of hypothyroid rats.…”

“…The reduced exocytosis efficiency (P13-P18) (Fig. 9D) (Sendin et al, 2007) and the lack of maturation of presynaptic proteins in IHCs of Pax8 Ϫ/Ϫ compared with control mice (Sendin et al, 2007) is in line with this conclusion. Given that in hypothyroid rat IHCs the presynaptic machinery stays similarly immature, the reduced exocytosis efficiency would alone impair hearing thresholds at an age of 4 weeks when Ca 2ϩ currents reach the low amplitudes of control IHCs.…”

“…3) (Beutner and Moser, 2001;Marcotti et al, 2003b) and (2) the expression of a small, very negatively activating K ϩ (KCNQ4) conductance that sets the resting potential in mature IHCs (Oliver et al, 2003). The retarded downregulation of the Ca 2ϩ conductance in TH-deficient IHCs clearly favors Ca 2ϩ APs, similar to the lack of KCNQ4 expression demonstrated in IHCs of Pax8 Ϫ/Ϫ mice (Sendin et al, 2007), which, for hypothyroid rats, needs to be confirmed.…”

“…In a parallel study, Sendin et al (2007) analyzed the effects of TH deficiency on the maturation of ion channels, presynaptic proteins, and exocytosis in Pax8 Ϫ/Ϫ mice.…”

Electrical Properties and Functional Expression of Ionic Channels in Cochlear Inner Hair Cells of Mice Lacking the α10 Nicotinic Cholinergic Receptor Subunit

“…Thus, contrary to the cessation of ACh sensitivity normally seen in wild-type mice at around P13-14 (Katz et al 2004), it persists up to 6 weeks after birth in Ca v1.3 knockout mice (Brandt et al 2003;Nemzou et al 2006). Moreover, during this critical developmental window, several studies have shown that modifications in the expression of proteins involved in thyroid hormone signaling alter IHC spiking activity, probably due to the lack of expression of BK and KCNQ4 channels together with an increase in calcium influx Brandt et al 2007;Sendin et al 2007). These data indicate that there is a concerted regulation of the functional expression of ion channels during IHC maturation.…”