Salleh Ehaideb will Present His Research July 11, 2013
CREATING AN EPILEPTIC FLY BY TIPPING THE BALANCE OF PRICKLE ISOFORMS
prickle participates in the non-canonical WNT signaling/planar cell polarity (PCP) pathway. We previously reported that fly prickle mutants are seizure-prone, and that mutations in Prickle orthologues are associated with seizures in flies, mice and humans. prickle encodes two adult isoforms, prickle (pk) and spiny legs (sple). Also, flies heterozygous for pksple mutations display pronounced seizures even though no planar cell polarity defects are visible, suggesting that the PCP and seizure phenotypes can be genetically separated. Moreover, the pkpk mutants are actually less seizure-prone than controls, which suggests that pk and sple act antagonistically. This was illustrated by targeted overexpression of the pkpk isoform in motor neurons and muscles (which recapitulates the imbalance of pk vs sple isoforms seen in the pksple heterozygote) strongly induces fly seizures in an otherwise wild-type fly. pksple mutants have neuroanatomical and electrophysiological defects, including increased numbers of terminal boutons at neuromuscular junctions with an increase in average bouton size. Both pksple and pkpk mutant flies show an increase in boutons number. Strikingly, pksple mutants show an increase in big bouton numbers, while pkpk mutant flies show an increase in small bouton numbers. Additionally, using the electroconvulsive seizure stimulation paradigm, we show that the pksple flies have a lowered seizure threshold even though excitatory junctional potentials at the NMJ are similar between the mutant and control flies. Finally, our immunofluorescent experiments show that pk is co-localizing with other proteins that are associated with synaptic vesicles at the neuromuscular junctons.