Synaptogenèse | EPFL Graph Search

La synaptogenèse est la formation des synapses. Bien qu'elle se produise tout au long de la durée de vie d'une personne saine, une explosion de la formation des synapses se produit au cours du développement précoce du cerveau. On prend pour exemple la mise en place de la jonction neuromusculaire. Étapes Tout d'abord, il doit y avoir une reconnaissance par les terminaisons axonales des cellules cibles avec lesquelles la jonction doit se faire. Grâce à un gradient moléculaires et de facteurs attractifs sécrétés notamment par des cellules gliales proche, les axones sont guidés dans leurs mouvements afin de trouver leur cellule cible. Dans un second temps, il faut établir un contact pré-synaptique, où le filopode contacte la cellule cible. Dès lors, l'élongation du dit-filipode va cesser et les autres filipodes en compétition vont se rétracter. En post-synaptique, un protéoglycane, l'agrine, permettant la différenciation de la jonction neuromusculaire mais aussi la croissance

Synaptic and Cellular Organization of Layer 1 of the Developing Rat Somatosensory Cortex

Shruti Muralidhar

In this thesis, we systematically characterised the circuitry, cellular composition and synaptic connectivity of layer 1 (L1) of the somatosensory cortex of juvenile rats (post natal days 13-16). Electrophysiological and morphological parameters were measured using single and multi-cell patch-clamp electrophysiology followed by histochemical staining and 3D morphological reconstruction. Guided by the Petilla convention, we classified cells in term of their firing patterns, identifying five electrophysiological types: classical Non-Accommodating Cells (cNAC), classical Accommodating Cells (cAC), burst Non-Accommodating Cells (bNAC), classical Stuttering cells (cSTUT) and classical Irregular Spiking cells (cIR). We created first a subjective and then an objective classification of different morphological cell types. The subjective classification identified the following types – NGC-DA, NGC-SA, HAC, DAC, LAC and SAC. The initial classification was refined and validated using PCA and LDA. We also studied connectivity patterns among L1 cells. Our results showed that a majority of the cells were connected by a slow GABAB mediated inhibitory connection, with a fast GABAA component. Multiple repetitions of stimulation produced a prominent run-down of postsynaptic potential amplitudes, which was not seen in perforated patch-clamp recordings that maintained the intracellular milieu. We propose that the run-down was due to the dilution of intracellular components and depletion of secondary messengers necessary for signalling of postsynaptic metabotropic GABAB receptor mediated responses. 3D morphological reconstructions of these pairs of cells, showed the presence of multi-synapse connections with an average of 9 putative contacts per detected electrophysiological connection. The average coupling co-efficient of gap junctions was 0.054 ± 0.03 with symmetrical conductance. In additional studies, we investigated patterns of inter-laminar connectivity, the modulation of apical dendritic activity by L1 neurons and patterns of gene expression in L1. We hope that the results these studies – single cell electrophysiology, morphology and connectivity analysis - provide useful hints for future studies of neocortical L1.

EPFL2013

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

Increased axonal bouton dynamics in the aging mouse cortex

Ge Gao, Graham Knott, Bohumil Maco

Aging is a major risk factor for many neurological diseases and is associated with mild cognitive decline. Previous studies suggest that aging is accompanied by reduced synapse number and synaptic plasticity in specific brain regions. However, most studies, to date, used either postmortem or ex vivo preparations and lacked key in vivo evidence. Thus, whether neuronal arbors and synaptic structures remain dynamic in the intact aged brain and whether specific synaptic deficits arise during aging remains unknown. Here we used in vivo two-photon imaging and a unique analysis method to rigorously measure and track the size and location of axonal boutons in aged mice. Unexpectedly, the aged cortex shows circuit-specific increased rates of axonal bouton formation, elimination, and destabilization. Compared with the young adult brain, large (i.e., strong) boutons show 10-fold higher rates of destabilization and 20-fold higher turnover in the aged cortex. Size fluctuations of persistent boutons, believed to encode long-term memories, also are larger in the aged brain, whereas bouton size and density are not affected. Our data uncover a striking and unexpected increase in axonal bouton dynamics in the aged cortex. The increased turnover and destabilization rates of large boutons indicate that learning and memory deficits in the aged brain arise not through an inability to form new synapses but rather through decreased synaptic tenacity. Overall our study suggests that increased synaptic structural dynamics in specific cortical circuits may be a mechanism for age-related cognitive decline.

National Academy of Sciences2013