Convulsions in worms mimic epileptic seizures

for nervous system defects. Although their nervous systems seemed to be organized correctly, the mutant worms were more susceptible to epilepsy-like convulsions than normal worms.

To induce convulsions, the researchers fed the mutant worms pentylenetetrazole (PTZ), a chemical that interferes with the activity of the most common type of inhibitory neurotransmitter, known as gamma-aminobutyric acid (GABA). By preventing GABA from inhibiting motor neurons, PTZ causes neuronal overexcitability, resulting in convulsions.

Although the doses of PTZ used in these experiments did not cause convulsions in normal worms, when the researchers administered the chemical to the mutant worms, the lower half of their bodies remained motionless, while muscles in the upper half contracted repeatedly, so the worms appeared to be bobbing their heads.

Since the number, placement, and organization of the GABA neurons in the mutant worms appeared normal, the team decided to look at the GABA neurons' ability to release neurotransmitters. By attaching a green fluorescent tag to a protein associated with the synaptic vesicles, the sacs that transport neurotransmitter molecules, the team was able to visualize those vesicles.

They carefully examined how vesicles lined up at the ends of nerve cells to release neurotransmitters. In normal worms, these sacs arranged themselves in an orderly fashion at the synapse, but in the LIS1-mutant worms, the researchers noticed gaps in the synaptic vesicle line-up.

The LIS1 protein interacts with a molecular motor protein called dynein, which helps transport the neurotransmitter vesicles within cells. In further experiments, the researchers found that blocking production of dynein caused similar convulsions and gaps in vesicle distribution as the LIS1 mutation. Caldwell's team now thinks that mutated LIS1 might misdirect the movement of synaptic vesicles. If vesicles fail to migrate properly to the end of the cell

Contact: Jennifer Donovan
Howard Hughes Medical Institute

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