Synthetic Ciguatoxin CTX 3C Induces a Rapid Imbalance in Neuronal Excitability

Abstract

Ciguatera is a human global disease caused by the consumption of contaminated fish that have accumulated ciguatoxins (CTXs), sodium channel activator toxins. Symptoms of ciguatera include neurological alterations such as paraesthesiae, dysaesthesiae, depression, and heightened nociperception, among others. An important issue to understand these long-term neurological alterations is to establish the role that changes in activity produced by CTX 3C represent to neurons. Here, the effects of synthetic ciguatoxin CTX 3C on membrane potential, spontaneous spiking, and properties of synaptic transmission in cultured cortical neurons of 11-18 days in vitro (DIV) were evaluated using electrophysiological approaches. CTX 3C induced a large depolarization that decreased neuronal firing and caused a rapid inward tonic current that was primarily GABAergic. Moreover, the toxin enhanced the amplitude of miniature postsynaptic inhibitory currents (mIPSCs), whereas it decreased the amplitude of miniature postsynaptic excitatory currents (mEPSCs). The frequency of mIPSCs increased, whereas the frequency of mEPSCs remained unaltered. We describe, for the first time, that a rapid membrane depolarization caused by CTX 3C in cortical neurons activates mechanisms that tend to suppress electrical activity by shifting the balance between excitatory and inhibitory synaptic transmission toward inhibition. Indeed, these results suggest that the acute effects of CTX on synaptic transmission could underlie some of the neurological symptoms caused by ciguatera in humans.

The Marine Guanidine Alkaloid Crambescidin 816 Induces Calcium Influx and Cytotoxicity in Primary Cultures of Cortical Neurons through Glutamate Receptors

“…These mEPSCs in cortical neurons were glutamatergic as previously described in this cellular model by their complete pharmacological blockade by the combination of APV and CNQX. 24 A representative recording of mEPSC before and after addition of 10 μM Cramb816 is shown in Figure 6A. Amplified recordings from the same neuron, before and after addition of the toxin, are shown in Figure 6B.…”

“…mEPSCs were confirmed by their complete inhibition in the presence of 20 μM CNQX and 100 μM APV as previously described. 24 Toxins and Drugs Used. Cramb816 was extracted and isolated from the Mediterranean sponge Crambe crambe.…”

Marine Neurotoxins: a Double-edged Sword in Food Industry and Brain Research

“…CTX toxicity is 100 times stronger than TTX. CTX is a new agonist of voltagedependent Na + channels that binds to the channel receptor site VI and increases the permeability of Na + to excite the cell membrane, causing strong depolarization, resulting in changes in neuromuscular excitability, inducing a series of pharmacological and toxicological effects [16][17][18] . Three types of CTX, Pacific cigarettes, Caribbean ciguatoxin, and Indian ciguatoxin have been found [19] .…”

Total synthesis and related studies of large, strained, and bioactive natural products

“…62,74,75) Synthetic CTXs have also accelerated studies on the mechanisms of CTX binding and the effects to voltage-sensitive sodium channels (VSSC) and other ion channels, 76–82) the symptomatology of CTX poisoning, and the long-term neurological symptoms caused by CTX poisoning. 83,84) …”