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, 276 (1-2), 70-8

Formation and Maturation of the Calyx of Held


Formation and Maturation of the Calyx of Held

Paul A Nakamura et al. Hear Res.


Sound localization requires precise and specialized neural circuitry. A prominent and well-studied specialization is found in the mammalian auditory brainstem. Globular bushy cells of the ventral cochlear nucleus (VCN) project contralaterally to neurons of the medial nucleus of the trapezoid body (MNTB), where their large axons terminate on cell bodies of MNTB principal neurons, forming the calyces of Held. The VCN-MNTB pathway is necessary for the accurate computation of interaural intensity and time differences; MNTB neurons provide inhibitory input to the lateral superior olive, which compares levels of excitation from the ipsilateral ear to levels of tonotopically matched inhibition from the contralateral ear, and to the medial superior olive, where precise inhibition from MNTB neurons tunes the delays of binaural excitation. Here we review the morphological and physiological aspects of the development of the VCN-MNTB pathway and its calyceal termination, along with potential mechanisms that give rise to its precision. During embryonic development, VCN axons grow towards the midline, cross the midline into the region of the presumptive MNTB and then form collateral branches that will terminate in calyces of Held. In rodents, immature calyces of Held appear in MNTB during the first few days of postnatal life. These calyces mature morphologically and physiologically over the next three postnatal weeks, enabling fast, high fidelity transmission in the VCN-MNTB pathway.


Figure 1
Figure 1. Summary of mutations affecting VCN-MNTB axon targeting
A, In wild type mice, VCN axons project to the contralateral MNTB only. B, VCN axons never reach the midline in DCC and netrin-1 deficient mice (Howell et al., 2007). DCC deficient mutant mice also have less VCN neurons than heterozygous and wild type littermates (Howell et al., 2007). C, VCN axons abnormally project to the ipsilateral, not contralateral, MNTB in Krox20::cre;Robo3 mutant mice (Renier et al., 2010). D, Mutations in Eph proteins that reduce reverse signaling through ephrin-B ligands include deletions of the intracellular domain of ephrin-B2 and null mutations in EphB2 and EphB3. These mutations result in a significant number of aberrant ipsilateral VCN-MNTB projections (Hsieh et al., 2010). E, When only the intracellular domain is deleted in EphB2, forward signaling is reduced while reverse signaling through ephrin-B2 is intact. These mice have normal, strictly contralateral VCN-MNTB projections (Hsieh et al., 2010), suggesting that reverse, but not forward, EphB/ephrin-B signaling regulates the precision of this pathway. F, In NB-2 knockout mice, a percentage of MNTB principal neurons lack calyces of Held, which increases the number of apoptotic neurons (red) in MNTB and VCN, compared to wild type mice (Toyoshima et al., 2009). Adapted, with permission, from Hsieh et al., 2010.

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