Modulating Behavior in C. elegans Using Electroshock and Antiepileptic Drugs

Abstract

The microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C. elegans, an assay for electroshock/electroconvulsion remains absent. Here, we have developed a quantitative behavioral method to assess the locomotor response following electric shock in C. elegans. Electric shock impairs normal locomotion, and induces paralysis and muscle twitching; after a brief recovery period, shocked animals resume normal locomotion. We tested electric shock responses in loss-of-function mutants for unc-25, which encodes the GABA biosynthetic enzyme GAD, and unc-49, which encodes the GABAA receptor. unc-25 and unc-49 mutants have decreased inhibitory GABAergic transmission to muscles, and take significantly more time to recover normal locomotion following electric shock compared to wild-type. Importantly, increased sensitivity of unc-25 and unc-49 mutants to electric shock is rescued by treatment with antiepileptic drugs, such as retigabine. Additionally, we show that pentylenetetrazol (PTZ), a GABAA receptor antagonist and proconvulsant in mammalian and C. elegans seizure models, increases susceptibility of worms to electric shock.

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

“…Electroshock involves application of voltage to animals suspended in saline buffer, and results in body convulsions and paralysis. Consistent with prior work, unc-25/GAD mutants (which lack inhibitory GABAergic transmission) display increased electroshock sensitivity with longer time to recovery (Figure 5D) (Risley et al, 2016). Recovery time was also increased in eel-1 mutants, and rescued by bggIs16 (Figure 5D).…”

“…Another behavior that is sensitive to E/I balance in the worm motor circuit is electroshock induced paralysis (Risley et al, 2016). Electroshock involves application of voltage to animals suspended in saline buffer, and results in body convulsions and paralysis.…”

egl-4 modulates electroconvulsive seizure duration in C. elegans

“…Our laboratory has used Retigabine with C. elegans in the past to show that human seizure therapeutics can successfully be used to alter recovery time in invertebrates; however, regarding N2, the drug must be used in conjunction with a chemical convulsant to induce an effect (Opperman et al 2017; Risley et al 2016). We hypothesize this is due to the increased seizure threshold for N2.…”

“…This procedure was performed as described previously (Risley et al 2016). In brief, 15 μL of standard M9 salt solution was added to 9 mm long segments of clear plastic tubing (Tygon® microbore tubing).…”

“…In addition, its small size, relatively inexpensive maintenance and short generation time provide a powerful platform to explore as a human seizure model. The past research in our laboratory has established a behavioral method to induce an electroconvulsive seizure (ES) in adult C. elegans (Risley et al 2016). With this method, we determined that the behavioral recovery from an ES is partly due to contribution of the major inhibitory neurotransmitter, GABA, in the nervous system.…”