The Cell Adhesion Molecule Neurofascin Stabilizes Axo-axonic GABAergic Terminals at the Axon Initial Segment

Abstract

Cell adhesion molecules regulate synapse formation and maintenance via transsynaptic contact stabilization involving both extracellular interactions and intracellular postsynaptic scaffold assembly. The cell adhesion molecule neurofascin is localized at the axon initial segment of granular cells in rat dentate gyrus, which is mainly targeted by chandelier cells. Lentiviral shRNA-mediated knockdown of neurofascin in adult rat brain indicates that neurofascin regulates the number and size of postsynaptic gephyrin scaffolds, the number of GABA A receptor clusters as well as presynaptic glutamate decarboxylase-positive terminals at the axon initial segment. By contrast, overexpression of neurofascin in hippocampal neurons increases gephyrin cluster size presumably via stimulation of fibroblast growth factor receptor 1 signaling pathways.

A Combined Transgenic Proteomic Analysis and Regulated Trafficking of Neuroligin-2

“…Neurofascin localizes specifically to inhibitory synapses on the axon initial segment (56), in contrast to NL2, which localizes more broadly to inhibitory synapses on the axon initial segment, perisomatic region, and dendrites. Functionally, in adult rat hippocampal neurons, altering levels of neurofascin altered the number and size of gephyrin and GABA receptor clusters and GABAergic innervation on the axon initial segment but not on dendrites (57). Ankyrin-2 borders the axon initial segment (58) and thus may also contribute to GABAergic synapse development in this specialized domain.…”

Dentate Gyrus Local Circuit is Implicated in Learning Under Stress—a Role for Neurofascin

“…Two independent lentiviral vectors sh252 and sh1504 were chosen in order to rule out off-target effects. Target sequences of both shRNA vectors were described in [7,8].…”

“…Construction, validation, and production of lentiviral vectors were described in [8]. Two independent lentiviral vectors sh252 and sh1504 were chosen in order to rule out off-target effects.…”

“…Neurofascin was shown to have a vital role in regulating the formation of gephyrin clusters and their translocation during development [7]. In the adult dentate gyrus, neurofascin expression is required for the stabilization of gephyrin clusters as well as GABA A receptors at the postsynaptic site and for the maintenance of presynaptic terminals [8].…”

Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABA A receptors

“…In the cerebellum, basket and stellar interneurons project specific axon terminals to the AISs of Purkinje cells, forming GABAergic "pinceau" synapses (10). Formation of these pinceau synapses depends on a steep gradient of the cell adhesion molecule neurofascin, which is enriched at the AIS (11,12). Both GABAergic pinceau synapses and the neurofascin gradient are missing in mice with cerebellar knockout out of the membrane adaptor ankyrin-G (11,13).…”