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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.<\/jats:p>","DOI":"10.1242\/jcs.182089","type":"journal-article","created":{"date-parts":[[2016,3,17]],"date-time":"2016-03-17T02:28:23Z","timestamp":1458181703000},"page":"1878-1891","source":"Crossref","is-referenced-by-count":32,"title":["Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels"],"prefix":"10.1242","volume":"129","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6272-1821","authenticated-orcid":false,"given":"Pierluigi","family":"Valente","sequence":"first","affiliation":[{"name":"University of Genova 1 Department of Experimental Medicine , , Viale Benedetto XV, 3, Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Lignani","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia 2 , Largo Rosanna Benzi 10 , Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8252-2595","authenticated-orcid":false,"given":"Lucian","family":"Medrihan","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia 2 , Largo Rosanna Benzi 10 , Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Bosco","sequence":"additional","affiliation":[{"name":"University of Genova 1 Department of Experimental Medicine , , Viale Benedetto XV, 3, Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5417-4722","authenticated-orcid":false,"given":"Andrea","family":"Contestabile","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia 2 , Largo Rosanna Benzi 10 , Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pellegrino","family":"Lippiello","sequence":"additional","affiliation":[{"name":"University of Genova 1 Department of Experimental Medicine , , Viale Benedetto XV, 3, Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Ferrea","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia 2 , Largo Rosanna Benzi 10 , Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8561-9037","authenticated-orcid":false,"given":"Melitta","family":"Schachner","sequence":"additional","affiliation":[{"name":"Center for Neuroscience, Shantou University Medical College 3 , 22 Xin Ling Road, Shantou, Guangdong 515041 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0653-8368","authenticated-orcid":false,"given":"Fabio","family":"Benfenati","sequence":"additional","affiliation":[{"name":"University of Genova 1 Department of Experimental Medicine , , Viale Benedetto XV, 3, Genova 16132 , Italy"},{"name":"Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia 2 , Largo Rosanna Benzi 10 , Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Gioved\u00ec","sequence":"additional","affiliation":[{"name":"University of Genova 1 Department of Experimental Medicine , , Viale Benedetto XV, 3, Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9599-3436","authenticated-orcid":false,"given":"Pietro","family":"Baldelli","sequence":"additional","affiliation":[{"name":"University of Genova 1 Department of Experimental Medicine , , Viale Benedetto XV, 3, Genova 16132 , Italy"},{"name":"Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia 2 , Largo Rosanna Benzi 10 , Genova 16132 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","reference":[{"key":"2024061316092782500_JCS182089C1","doi-asserted-by":"crossref","first-page":"4764","DOI":"10.1523\/JNEUROSCI.13-11-04764.1993","article-title":"Several extracellular domains of the neural cell adhesion molecule L1 are involved in neurite outgrowth and cell body adhesion","volume":"13","author":"Appel","year":"1993","journal-title":"J. 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