000154776 001__ 154776
000154776 005__ 20180501105942.0
000154776 0247_ $$2doi$$a10.5075/epfl-thesis-4938
000154776 02470 $$2urn$$aurn:nbn:ch:bel-epfl-thesis4938-9
000154776 02471 $$2nebis$$a6203278
000154776 037__ $$aTHESIS_LIB
000154776 041__ $$aeng
000154776 088__ $$a4938
000154776 245__ $$aIdentification of Signaling Mechanisms Determining the Development of Large Excitatory Synapses in the Lower Auditory System
000154776 269__ $$a2011
000154776 260__ $$aLausanne$$bEPFL$$c2011
000154776 300__ $$a117
000154776 336__ $$aTheses
000154776 520__ $$aIn the brainstem auditory circuit of mammals and birds,       excitatory synapses with extraordinarily large size have       evolved, which ensure fast membrane potential signaling       mediated by large, multiquantal excitatory postsynaptic       currents (EPSCs). The so-called "calyx of Held" synapses are       formed by the globular bushy cells (GBCs) in the ventral       cochlear nucleus (VCN) onto the contralateral medial nucleus       of the trapezoid body (MNTB) neurons. One the other hand, the       spherical bushy cells (SBCs) in the VCN project to the       lateral superior olive (LSO), where they form small       bouton-like synapses. Therefore, the lower auditory brainstem       circuits constitute an example of synapse-specificity, in       which presynaptic neuron pools are connected through highly       specific synapses to their postsynaptic partner neurons.       Calyx of Held synapses are formed at postnatal day 2 - 4 in       rodents in a target-cell specific manner and prior to the       onset of hearing. The molecular signaling pathways which       drive the formation of these synapses are unknown. Here we identify bone morphogenetic protein (BMP)       signaling as an essential signaling pathway in the       development of calyces of Held. Through unbiased genome-wide       transcriptome analyses in rats and mice, BMPs were identified       as candidates for diffusible signaling molecules which are       expressed at a higher level in the MNTB (the target area of       calyces of Held), as compared to the LSO. The microarray       analysis was validated by quantitative PCR (qPCR) and       in-situ hybridisation. A conditional knock-out (KO) of       BMP-receptor 1a (BMPR1a) in the lower auditory system, in the       genetic background of a conventional KO of BMP-receptor 1b       (BMPR1b), was then used to address the role of BMP-receptor       signaling for calyx of Held formation in vivo.       Genetically knocking out BMPR1a/1b activity in the auditory       brainstem led to a drastic deficit at the calyx of Held       synapses both morphologically and functionally, as well as to       the persistence of multiple innervation of MNTB neurons. This study therefore shows that BMP signaling drives the       development of the large calyx of Held synapses. The study       offers a possible mechanism for the specificity of a large       excitatory synapse formation in the central nervous systems       (CNS). In addition, the study shows a novel function of BMP       signaling in synaptogenesis in the mammalian CNS.
000154776 6531_ $$acalyx of Held
000154776 6531_ $$asynaptogenesis
000154776 6531_ $$asynapse specificity
000154776 6531_ $$abone morphogenetic proteins
000154776 6531_ $$aneuronal circuits
000154776 6531_ $$asynaptic transmission
000154776 700__ $$0244907$$aXiao, Le$$g170204
000154776 720_2 $$0244726$$aSchneggenburger, Ralf$$edir.$$g169973
000154776 8564_ $$s4844513$$uhttps://infoscience.epfl.ch/record/154776/files/EPFL_TH4938.pdf$$yTexte intégral / Full text$$zTexte intégral / Full text
000154776 909C0 $$0252339$$pLSYM$$xU11233
000154776 909CO $$ooai:infoscience.tind.io:154776$$pDOI$$pthesis$$pthesis-bn2018$$pDOI2$$pSV
000154776 918__ $$aSV$$cBMI$$dEDNE
000154776 919__ $$aLSYM
000154776 920__ $$b2011
000154776 970__ $$a4938/THESES
000154776 973__ $$aEPFL$$sPUBLISHED
000154776 980__ $$aTHESIS