Serotonergic dystrophy induced by excess serotonin

Abstract

Administration of certain serotonin-releasing amphetamine derivatives (fenfluramine and/or 3,4-methylenedioxymethamphetamine, MDMA, 'ecstasy') results in dystrophic serotonergic morphology in the mammalian brain. In addition to drug administration, dystrophic serotonergic neurites are also associated with neurodegenerative disorders. We demonstrate here that endogenously elevated serotonin in the Drosophila CNS induces aberrant enlarged varicosities, or spheroids, that are morphologically similar to dystrophic mammalian serotonergic fibers. In Drosophila these spheroids are specific to serotonergic neurons, distinct from typical varicosities, and form only after prolonged increases in cytoplasmic serotonin. Our results also suggest that serotonin levels during early development determine later sensitivity of spheroid formation to manipulations of the serotonin transporter (SERT). Elevated serotonin also interacts with canonical protein aggregation and autophagic pathways to form spheroids. The data presented here support a model in which excess cytoplasmic neurotransmitter triggers a cell-specific pathway inducing aberrant morphology in fly serotonergic neurons that may be shared in certain mammalian pathologies.

Serotonin: a regulator of neuronal morphology and circuitry

“…Fenfluramine, one component of the anorectic drug combination, Fen-Phen, has similar mechanistic effects on serotonergic neurons as MDMA, and also induces regionally specific serotonergic degeneration in mammals [84,85]. Enhanced serotonin production in Drosophila larvae induces similar degenerative-like swellings along serotonergic branches [86]. As was also observed in mammals, the serotonergic cell bodies of the Drosophila larvae were spared, however, unlike the rodent condition, no loss of serotonergic fibers was observed [86].…”

“…Enhanced serotonin production in Drosophila larvae induces similar degenerative-like swellings along serotonergic branches [86]. As was also observed in mammals, the serotonergic cell bodies of the Drosophila larvae were spared, however, unlike the rodent condition, no loss of serotonergic fibers was observed [86]. Substituted amphetamines induce efflux of serotonin from neurons [87], therefore it is unclear whether serotonergic fibers are truly lost following drug administration, as mammalian models to date have utilized serotonergic marker immunoreactivity to assess serotonergic fiber distribution [81,82,84,85].…”

“…Both MDMA and fenfluramine cause release of serotonin both intracellularly and extracellularly by action at the vesicular transporter (VMAT) and SERT [87,88] and evidence suggests increases in cytoplasmic serotonin are responsible for serotonergic dystrophy in flies synthesizing excess serotonin [86]. There is precedence for receptor independent signaling cascades that are initiated by cytoplasmic serotonin (Box 1) and it will be interesting to ask whether this novel mechanism contributes to degenerative morphology in drug-administered mammals and flies producing excess serotonin.…”

Big Lessons from Tiny Flies:<em> Drosophila Melanogaster </em>as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

“…Overexpression of TRH in serotonergic neurons results in increased cytoplasmic serotonin levels, leading to spheroid formation, i.e. large aberrant swelling in neurites [106]. Interestingly, this TRH overexpression-mediated spheroid formation is specific to serotonergic neurons: TRH overexpression in dopaminergic neurons, which also express DDC and hence produce serotonin, does not result in spheroid formation [106].…”

“…large aberrant swelling in neurites [106]. Interestingly, this TRH overexpression-mediated spheroid formation is specific to serotonergic neurons: TRH overexpression in dopaminergic neurons, which also express DDC and hence produce serotonin, does not result in spheroid formation [106]. Mutation in DDC causes extensive branching of serotonergic axonal arborizations in larvae [107].…”