title: Homeostatic regulation of NCAM polysialylation is critical for correct synaptic targeting.
abstract: During development, axonal projections have a remarkable ability to innervate correct dendritic subcompartments of their target neurons and to form regular neuronal circuits. Altered axonal targeting with formation of synapses on inappropriate neurons may result in neurodevelopmental sequelae, leading to psychiatric disorders. Here we show that altering the expression level of the polysialic acid moiety, which is a developmentally regulated, posttranslational modification of the neural cell adhesion molecule NCAM, critically affects correct circuit formation. Using a chemically modified sialic acid precursor (N-propyl-D: -mannosamine), we inhibited the polysialyltransferase ST8SiaII, the principal enzyme involved in polysialylation during development, at selected developmental time-points. This treatment altered NCAM polysialylation while NCAM expression was not affected. Altered polysialylation resulted in an aberrant mossy fiber projection that formed glutamatergic terminals on pyramidal neurons of the CA1 region in organotypic slice cultures and in vivo. Electrophysiological recordings revealed that the ectopic terminals on CA1 pyramids were functional and displayed characteristics of mossy fiber synapses. Moreover, ultrastructural examination indicated a "mossy fiber synapse"-like morphology. We thus conclude that homeostatic regulation of the amount of synthesized polysialic acid at specific developmental stages is essential for correct synaptic targeting and circuit formation during hippocampal development.
authors: Institute for Microanatomy and Neurobiology, University Medical Center of the J. Gutenberg, University Mainz, Germany. johannes.vogt@unimedizin-mainz.de
authors: Johannes
authors: J
authors: Vogt
authors: Robert
authors: R
authors: Glumm
authors: Leslie
authors: L
authors: Schlüter
authors: Dietmar
authors: D
authors: Schmitz
authors: Benjamin R
authors: BR
authors: Rost
authors: Nora
authors: N
authors: Streu
authors: Benjamin
authors: B
authors: Rister
authors: B
authors: B
authors: Suman Bharathi
authors: Daniel
authors: D
authors: Gagiannis
authors: Herbert
authors: H
authors: Hildebrandt
authors: Birgit
authors: B
authors: Weinhold
authors: Martina
authors: M
authors: Mühlenhoff
authors: Thomas
authors: T
authors: Naumann
authors: Nic E
authors: NE
authors: Savaskan
authors: Anja U
authors: AU
authors: Brauer
authors: Werner
authors: W
authors: Reutter
authors: Bernd
authors: B
authors: Heimrich
authors: Robert
authors: R
authors: Nitsch
authors: Rüdiger
authors: R
authors: Horstkorte
mesh_terms: D000818:Animals; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D012794:Sialic Acids / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D019006:Neural Cell Adhesion Molecules; D012794:Sialic Acids; C021319:polysialic acid