000154776 001__ 154776
000154776 005__ 20190316234931.0
000154776 0247_ $$2doi$$a10.5075/epfl-thesis-4938
000154776 02470 $$2urn$$aurn:nbn:ch:bel-epfl-thesis4938-9
000154776 02471 $$2nebis$$a6203278
000154776 037__ $$aTHESIS
000154776 041__ $$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$$pthesis$$pthesis-bn2018$$pDOI$$pSV$$qDOI2$$qGLOBAL_SET
000154776 918__ $$aSV$$cBMI$$dEDNE
000154776 919__ $$aLSYM
000154776 920__ $$b2011
000154776 970__ $$a4938/THESES
000154776 973__ $$aEPFL$$sPUBLISHED
000154776 980__ $$aTHESIS