, 2007; see Chédotal, 2011 for a review). Interestingly, DCC has been shown to associate with the protein synthesis machinery and to regulate protein translation in axons ( Brittis et al., 2002; Tcherkezian et al., 2010). Therefore, a dysregulation of axonal protein synthesis following a failure of axon midline crossing could lead to expression changes of presynaptic proteins, and/or trophic factors relevant for the maturation of synapse function. It was shown recently that the absence of RIM1 and RIM2 proteins at the calyx of Held results in a marked reduction of presynaptic

Ca2+ currents, and a smaller fast-releasable vesicle pool ( Han et al., 2011). The variable Ca2+ current density and smaller vesicle pools observed here in Robo3 cKO mice are reminiscent of the RIM1/2

KO phenotype. Everolimus chemical structure It is possible that the decreased presynaptic function of calyx synapses of Robo3 cKO mice is the consequence of reduced levels of RIM protein, or of other proteins involved in the functional organization of active zones ( Schoch and Gundelfinger, BVD-523 research buy 2006). It is noteworthy that while functional maturation of Ca2+ channel-release coupling is well documented at the calyx synapse ( Chuhma et al., 2001; Fedchyshyn and Wang, 2005; Taschenberger and von Gersdorff, 2000), the underlying changes in presynaptic protein expression and/or post-translational changes of presynaptic proteins are largely unknown (but see Yang et al., 2010). We observed that the functional maturation of

most calyces of Held was defective in Robo3 cKO mice, while the initial formation of the typical calyx structure, despite a moderate synapse elimination deficit, was largely unchanged. Therefore, it seems that a program of morphological Mephenoxalone growth of calyces was not strongly affected in Robo3 cKO mice. It has been shown that unilateral inner ear removal and the ensuing degeneration of the cochlear nucleus and denervation of the contralateral MNTB, leads to sprouting of GBC axons which can form ipsilateral calyces of quite typical morphology (Hsieh et al., 2007; Kitzes et al., 1995). In this denervation paradigm, a program of morphological calyx formation also seems to take place readily. Of note, denervation-induced ipsilateral calyces arise from axons that have already successfully crossed the midline. Therefore, ipsilateral calyces formed after denervation might show normal functional maturation, a possibility that should be tested in future work. The trophic factors and signaling molecules that drive the morphological development of the highly specialized calyx-type synapses, which are found on several levels of the lower auditory system (Grothe et al., 2010), are just beginning to be investigated (Nakamura and Cramer, 2011).