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. Highlighted Article: We uncovered a new role of L1CAM in the functional expression and localization of Na+ channels to the plasma membrane, ensuring correct initiation of action potential and normal firing activity.