Synapse | EPFL Graph Search

In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from one neuron to another. Neurons are specialized to pass signals to individual target cells, and synapses are the means by which they do so. At a synapse, the plasma membrane of the signal-passing neuron (the presynaptic neuron) comes into close apposition with the membrane of the target (postsynaptic) cell. Both the presynaptic and postsynaptic sites contain extensive arrays of molecular machinery that link the two membranes together and carry out the signaling process. In many synapses, the presynaptic part is located on an axon and the postsynaptic part is located on a dendrite or soma. Astrocytes also exchange information with the synaptic neurons, responding to synaptic activity and, in turn, regulating neurotransmission. Synapses (at leas

Genetic dissection of the role of BMP signaling for the development of the auditory brainstem nuclei and the large calyx of Held synapse

Elin Kristina Kronander

Synapses are key elements for communication within the complex network of neurons that make up our brain. Interestingly, synaptic connections can differ greatly in form and function, depending on the specific circuit into which they are embedded. In this PhD thesis, I use a large excitatory synaptic connection in the auditory brainstem, the calyx of Held, as a model to study the molecular mechanisms of synapse development. We are especially interested in the role of bone morphogenetic protein (BMP) signaling in this process. BMPs are extracellular morphogens with signaling roles early in the development of multicellular animals, and in brain development. In the first part of this PhD thesis, I have established an organotypic culture model of the auditory brainstem, in which large calyx-like synapses form in vitro. I could demonstrate the usefulness of this culture system for studying molecular mechanisms of nerve terminal growth, by showing that the BMP-receptor inhibitor, LDN-193189, leads to a reduction in the size of nerve terminals forming in vitro. In the second part, I have used mouse genetics, especially floxed alleles of BMP-receptors and the SMAD4 protein, coupled with morphological analysis and electrophysiological measurements, to investigate the role of BMP signaling in the development of large calyx of Held nerve terminals. Genetic inactivation of BMP type I receptors early-on (~ embryonic day 9 (E9) led to a significantly smaller ventral cochlear nucleus (VCN) and medial nucleus of the trapezoid body (MNTB), indicating that BMP signaling is involved in the histogenesis of these auditory brainstem nuclei. These deficits were in part caused by the intracellular SMAD - signaling pathway, as revealed by conditional inactivation of the SMAD4 gene. To circumvent morphological changes observed upon the early inactivation of BMP receptors, I investigated the onset of Cre expression in a Parvalbumin (PV) Cre mouse line where recombination happens in presynaptic VCN neurons at ~ E15, and in postsynaptic MNTB neurons at postnatal day (P) 6. Conditional inactivation of BMP-receptors using the PVCre mouse line did not lead to morphological alterations. However, in these conditional KO mice, the functional development of the calyx of Held synapse was not significantly altered when measured at P6 (only the presynaptic receptors should be removed), nor at P14 or at P21, at which both pre- and postsynaptic receptors should be removed. Thus, presynaptic BMP-receptor activation alone seems unlikely to be necessary for calyx of Held growth. Also, ongoing BMP-signaling in both pre- and postsynaptic compartments seems dispensable for later maturation processes and the maintenance of the calyx of Held synapse. Finally, I removed BMP receptors specifically in the presynaptic neuron pool via virus-mediated expression of Cre-recombinase in newborn mice. I then observed subtle changes in the branching pattern of presynaptic axons and a slight increase in double-innervations. Taken together, this study shows that BMP signaling plays a role in the histogenesis of auditory brainstem structures and partially in the growth of calyx of Held synapses and elimination of competing synaptic connections. This work also offers a deeper understanding into the use of mouse genetic tools for studying the development of specific synaptic connections and establishes a novel culture model for studying such connections in vitro.

EPFL2016

Identification of Signaling Mechanisms Determining the Development of Large Excitatory Synapses in the Lower Auditory System

Le Xiao

In 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.

EPFL2011

Robo3-Driven Axon Midline Crossing Conditions Functional Maturation of a Large Commissural Synapse

Zsolt Norbert Babai, Ralf Schneggenburger

During the formation of neuronal circuits, axon pathfinding decisions specify the location of synapses on the correct brain side and in correct target areas. We investigated a possible link between axon midline crossing and the subsequent development of output synapses formed by these axons. Conditional knockout of Robo3 in the auditory system forced a large commissural synapse, the calyx of Held, to be exclusively formed on the wrong, ipsilateral side. lpsilateral calyx of Held synapses showed strong transmission defects, with reduced and desynchronized transmitter release, fewer fast-releasable vesicles, and smaller and more variable presynaptic Ca2+ currents. Transmission defects were not observed in a downstream inhibitory synapse, and some defects persisted into adulthood. These results suggest that axon midline crossing conditions functional maturation of commissural synapses, thereby minimizing the impact of mislocalized synapses on information processing. This mechanism might be relevant to human disease caused by mutations in the ROBO3 gene.

Elsevier2013