Thus, topographic information for axon-target interactions within the MNTB are preserved, even when axons form

synapses in the wrong hemisphere. However, functional maturation of the synaptic contacts was severely impaired. In wild-type animals, calyx of Held synapses acquire characteristic morphological and functional properties during the first 3 postnatal weeks. Each MNTB neuron is DAPT price innervated by a single calyx, and calyces exhibit extraordinarily fast transmitter release properties. In Robo3 conditional knockout mice, the ipsilaterally misplaced synapses were markedly underdeveloped by functional and morphological criteria. In 9- to 12-day-old animals, MNTB neurons were innervated by multiple smaller calyx-like terminals. Evoked transmission was severely reduced, and synapses showed immature forms of synaptic plasticity. In adolescent and adult animals, some of these defects were corrected, as multi-innervation receded and synapse size appeared normal. However, synaptic transmission remained strongly reduced, most likely due to a persistent decrease in the fast-releasable

pool of synaptic vesicles. A key question resulting from these findings is whether synapse development is indeed altered due to a failure of commissural neuron reprogramming after midline crossing or whether Robo3 has a postnatal selleck chemicals function in synaptogenesis. Robo3 is strongly downregulated during late embryonic development and not detectable during the postnatal period when calyces develop (Michalski et al., 2013). Moreover, conditional ablation of Robo3 at the time

of birth did not alter synaptogenesis. Thus, the postnatal defects in synapse maturation are indeed a consequence of the Robo3 loss-of-function during embryonic development. The authors propose that axon midline crossing “conditions” synapse maturation. According to this model, midline crossing Isotretinoin would be a prerequisite for normal synapse development due to reprogramming of gene expression and/or protein trafficking in the commissural neurons. An additional interpretation would be that the inappropriate ipsilateral convergence of VCN-derived information with other neuronal activities causes the developmental changes. However, phenotypes emerge before hearing onset (postnatal day 12), and other synapses such as MNTB-LSO connections develop normally. This supports a rather selective defect in the misrouted VCN-MNTB connections. The key targets of the presumptive midline-dependent re-programming remain to be identified. However, several molecular signals that direct the growth and functional properties of calyx of Held synapses have emerged in recent studies. Thus, mouse mutants lacking the active zone proteins RIM1 and RIM2 exhibit a reduction in the fast-releasable pool of synaptic vesicles (Han et al., 2011).