Neural Development; Synapse Formation; Cell adhesion; Mouse genetics; Neuronal signaling mechanisms; nervous system; cerebellum; autism
Baudouin Stéphane J, Gaudias Julien, Gerharz Stefan, Hatstatt Laetitia, Zhou Kuikui, Punnakkal Pradeep, Tanaka Kenji F, Spooren Will, Hen Rene, De Zeeuw Chris I, Vogt Kaspar, Scheiffele Peter (2012), Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism., in Science (New York, N.Y.)
, 338(6103), 128-32.
Kalinovsky Anna, Boukhtouche Fatiha, Blazeski Richard, Bornmann Caroline, Suzuki Noboru, Mason Carol A, Scheiffele Peter (2011), Development of axon-target specificity of ponto-cerebellar afferents., in PLoS biology
, 9(2), 1001013-1001013.
Iijima Takatoshi, Wu Karen, Witte Harald, Hanno-Iijima Yoko, Glatter Timo, Richard Stéphane, Scheiffele Peter (2011), SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1., in Cell
, 147(7), 1601-14.
Panzanelli Patrizia, Gunn Benjamin G, Schlatter Monika C, Benke Dietmar, Tyagarajan Shiva K, Scheiffele Peter, Belelli Delia, Lambert Jeremy J, Rudolph Uwe, Fritschy Jean-Marc (2011), Distinct mechanisms regulate GABAA receptor and gephyrin clustering at perisomatic and axo-axonic synapses on CA1 pyramidal cells., in The Journal of physiology
, 589(Pt 20), 4959-80.
Asante Curtis Oware, Chu Amy, Fisher Mark, Benson Leora, Beg Asim, Scheiffele Peter, Martin John (2010), Cortical control of adaptive locomotion in wild-type mice and mutant mice lacking the ephrin-Eph effector protein alpha2-chimaerin., in Journal of neurophysiology
, 104(6), 3189-202.
Shen Kang, Scheiffele Peter (2010), Genetics and cell biology of building specific synaptic connectivity., in Annual review of neuroscience
, 33, 473-507.
Scheiffele Peter, Beg Asim A (2010), Neuroscience: Angelman syndrome connections., in Nature
, 468(7326), 907-8.
Scheiffele Peter, Yuzaki Michizuke (2010), Recent excitements about excitatory synapses., in The European journal of neuroscience
, 32(2), 179-80.
Tanaka Kenji F, Ahmari Susanne E, Leonardo E David, Richardson-Jones Jesse W, Budreck Elaine C, Scheiffele Peter, Sugio Shouta, Inamura Naoko, Ikenaka Kazuhiro, Hen René (2010), Flexible Accelerated STOP Tetracycline Operator-knockin (FAST): a versatile and efficient new gene modulating system., in Biological psychiatry
, 67(8), 770-3.
Dean Camin, Scheiffele Peter (2009), Imaging synaptogenesis by measuring accumulation of synaptic proteins., in Cold Spring Harbor protocols
, 2009(11), 5315-5315.
The assembly of functional neuronal circuits during development of the central nervous system requires an array of selective cell-cell interactions. These interactions direct cell migration, targeted growth and branching of axonal and dendritic processes, recognition of appropriate target cells, differentiation of pre- and postsynaptic structures, and recruitment of synapse-specific release machinery and neurotransmitter receptors. The aim of our studies is to understand the molecular mechanisms underlying the formation of specific connections between neurons in the central nervous system. In particular, we are examining the trans-synaptic signals that coordinate the choice of synaptic partners, assembly of synaptic junctions and stabilization of appropriate contacts. To address these questions, we are using a combination of functional in vitro assays that facilitate the identification of new signaling mechanisms and in vivo analysis of neuronal circuits in the mouse cerebellum. The cerebellum is an excellent model system for the analysis of synaptic specificity due to it’s highly organized and well understood mature connectivity. Moreover, we have established a collection of genetic labeling and marking techniques that further facilitate dissection of synaptic specificity in a vertebrate in vivo system. Over the past years, we characterized the function of a family of neuronal cell adhesion molecules, called neuroligins and neurexins that form a heterophilic cell adhesion complex and that have potent synapse-organizing activities. These activities are regulated through extensive alternative splicing in sequences encoding the extracellular domains of these proteins. In our ongoing projects we are applying a combination of cell biological, biochemical, genetic and anatomical approaches to explore the molecular mechanisms of isoform-specific functions. Specifically, we will test the hypothesis that alternative splicing of neuroligin and neurexin isoforms underlies cell type- and synapse-specific trans-synaptic interactions in neuronal circuits of the mouse cerebellum. In further studies on the mechanisms underlying synaptic specificity in the mouse cerebellum we will examine a novel role for Bone Morphogenetic Proteins and their receptors in trans-synaptic signaling.The following projects will be the main focus of the research in my laboratory for the coming years and are described in detail in the Research Plan.(1) Coupling of Postsynaptic Neurotransmitter Complexes to Synaptic Adhesion Molecules: We previously observed highly selective association and function of specific neuroligin isoforms at GABAergic and glutamatergic synapses in vitro. In this project we will determine the structural and functional basis for these isoform-specific functions.(2) Molecular Diversity of Neurexins: With over 3,000 isoforms, the Neurexins represent one of the molecularly most diverse families of neuronal cell surface proteins in vertebrates. Our previous studies suggest that neurexin splice isoform diversity underlies a synapse-specific adhesive code. In this project we will perform single cell and population studies in genetically identified cerebellar neurons to examine the contribution of neurexin variants to neuronal identity and the selective wiring of cerebellar circuits.(3) Regulation of Alternative Splicing of the Neurexin Gene Family: In this project we are analyzing the molecular machinery that regulates neurexin splice isoform choice. We are particularly focusing on the selection of exon 20, an alternative exon that has determines the biochemical interactions between neurexins and specific neuroligin isoforms. To this end, we have identified an alternative splicing factor that associates with neurexin-1 mRNA and that is essential for the regulation of neurexin alternative splicing in vivo.(4) Emergence of synaptic specificity in the ponto-cerebellar projection system: We will use a combination of conditional mutant mice and gene transfer by in utero electroporation to examine the molecular mechanisms underlying selective axon-target interactions of cerebellar mossy fibers.