title: Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels.
abstract: L1 (also known as L1CAM) is a trans-membrane glycoprotein mediating neuron-neuron adhesion through homophilic and heterophilic interactions. Although experimental evidence has implicated L1 in axonal outgrowth, fasciculation and pathfinding, its contribution to voltage-gated Na(+) channel function and membrane excitability has remained unknown. Here, we show that firing rate, single cell spiking frequency and Na(+) current density are all reduced in hippocampal excitatory neurons from L1-deficient mice both in culture and in slices owing to an overall reduced membrane expression of Na(+) channels. Remarkably, normal firing activity was restored when L1 was reintroduced into L1-deficient excitatory neurons, indicating that abnormal firing patterns are not related to developmental abnormalities, but are a direct consequence of L1 deletion. Moreover, L1 deficiency leads to impairment of action potential initiation, most likely due to the loss of the interaction of L1 with ankyrin G that produces the delocalization of Na(+) channels at the axonal initial segment. We conclude that L1 contributes to functional expression and localization of Na(+) channels to the neuronal plasma membrane, ensuring correct initiation of action potential and normal firing activity.
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, Genova 16132, Italy.
authors.forename: Pierluigi
authors.identifier: 0000-0001-6272-1821
authors.initials: P
authors.lastname: Valente
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova 16132, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Lignani
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova 16132, Italy.
authors.forename: Lucian
authors.identifier: 0000-0002-8252-2595
authors.initials: L
authors.lastname: Medrihan
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, Genova 16132, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Bosco
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova 16132, Italy.
authors.forename: Andrea
authors.identifier: 0000-0002-5417-4722
authors.initials: A
authors.lastname: Contestabile
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, Genova 16132, Italy.
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Lippiello
authors.affiliation: Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova 16132, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Ferrea
authors.affiliation: Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong 515041, China.
authors.forename: Melitta
authors.identifier: 0000-0001-8561-9037
authors.initials: M
authors.lastname: Schachner
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, Genova 16132, Italy Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova 16132, Italy.
authors.forename: Fabio
authors.identifier: 0000-0002-0653-8368
authors.initials: F
authors.lastname: Benfenati
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, Genova 16132, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giovedì
authors.affiliation: Department of Experimental Medicine, University of Genova, Viale Benedetto XV, 3, Genova 16132, Italy Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, Genova 16132, Italy pietro.baldelli@unige.it.
authors.forename: Pietro
authors.identifier: 0000-0001-9599-3436
authors.initials: P
authors.lastname: Baldelli
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D061566:Voltage-Gated Sodium Channels / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D061566:Voltage-Gated Sodium Channels
keywords: Action potential; Adhesion molecule; CRASH syndrome; Firing activity; L1CAM; Sodium channels