Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels

• Published in: Journal of cell science Vol. 129; no. 9; pp. 1878 - 1891
• Main Authors: Valente, Pierluigi, Lignani, Gabriele, Medrihan, Lucian, Bosco, Federica, Contestabile, Andrea, Lippiello, Pellegrino, Ferrea, Enrico, Schachner, Melitta, Benfenati, Fabio, Giovedì, Silvia, Baldelli, Pietro
• Format: Journal Article
• Language: English
• Published: England 01.05.2016
• Subjects: Animals; Cell Membrane - genetics; Cell Membrane - metabolism; Gene Expression Regulation - physiology; Hippocampus - cytology; Hippocampus - metabolism; Mice; Mice, Knockout; Neural Cell Adhesion Molecule L1 - genetics; Neural Cell Adhesion Molecule L1 - metabolism; Neurons - cytology; Neurons - metabolism; Voltage-Gated Sodium Channels - biosynthesis; Voltage-Gated Sodium Channels - genetics; Sodium channels; Action potential; Adhesion molecule; Firing activity; L1CAM; CRASH syndrome
• ISSN: 1477-9137
• DOI: 10.1242/jcs.182089

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.