Impact of nuclear distribution element genes in the typical and atypical antipsychotics effects on nematode Caenorhabditis elegans: Putative animal model for studying the pathways correlated to schizophrenia.

The nuclear distribution element genes are conserved from fungus to humans. The nematode Caenorhabditis elegans expresses two isoforms of nuclear distribution element genes, namely nud-1 and nud-2. While nud-1 was functionally demonstrated to be the worm nudC ortholog, bioinformatic analysis revealed that the nud-2 gene encodes the worm ortholog of the mammalian NDE1 (Nuclear Distribution Element 1 or NudE) and NDEL1 (NDE-Like 1 or NudEL) genes, which share overlapping roles in brain development in mammals and also mediate the axon guidance in mammalian and C. elegans neurons. A significantly higher NDEL1 enzyme activity was shown in treatment non-resistant compared to treatment resistant SCZ patients, who essentially present response to the therapy with atypical clozapine but not with typical antipsychotics. Using C. elegans as a model, we tested the consequence of nud genes suppression in the effects of typical and atypical antipsychotics. To assess the role of nud genes and antipsychotic drugs over C. elegans behavior, we measured body bend frequency, egg laying and pharyngeal pumping, which traits are controlled by specific neurons and neurotransmitters known to be involved in SCZ, as dopamine and serotonin. Evaluation of metabolic and behavioral response to the pharmacotherapy with these antipsychotics demonstrates an important unbalance in serotonin pathway in both nud-1 and nud-2 knockout worms, with more significant effects for nud-2 knockout. The present data also show an interesting trend of mutant knockout worm strains to present a metabolic profile closer to that observed for the wild-type animals after the treatment with the typical antipsychotic haloperidol, but which was not observed for the treatment with the atypical antipsychotic clozapine. Paradoxically, behavioral assays showed more evident effects for clozapine than for haloperidol, which is in line with previous studies with rodent animal models and clinical evaluations with SCZ patients. In addition, the validity and reliability of using this experimental animal model to further explore the convergence between the dopamine/serotonin pathways and neurodevelopmental processes was demonstrated here, and the potential usefulness of this model for evaluating the metabolic consequences of treatments with antipsychotics is also suggested.

Pubmed ID: 30578843