title: Chronic ciguatoxin treatment induces synaptic scaling through voltage gated sodium channels in cortical neurons.
abstract: Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10-13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin. These findings identify an unanticipated role for ciguatoxin in the regulation of homeostatic plasticity in central neurons involving NaV channels and raise the possibility that some of the neurological symptoms of ciguatera might be explained by these compensatory mechanisms.
authors.affiliation: †Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Martín
authors.affiliation: †Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Vale
authors.affiliation: †Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Rubiolo
authors.affiliation: †Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Roel
authors.affiliation: ‡Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirama
authors.affiliation: ‡Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: §Departamento de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: Mercedes R
authors.initials: MR
authors.lastname: Vieytes
authors.affiliation: †Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: Luís M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology*; D002922:Ciguatoxins / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D061566:Voltage-Gated Sodium Channels; C466858:ciguatoxin 3C; D002922:Ciguatoxins