Opposing effects of catecholaminergic and serotoninergic systems in C. elegans: Potential implications for human posttraumatic stress disorders

BLANCO MG; VEUTHEY T; ANDERSEN N; RAYES D; DE ROSA MJ

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedades de Biociencias

Post-traumatic stress disorder (PTSD) is a clinical condition characterized by recurrent disrupting memories of a traumatic event,hyperarousal and anxiety. Despite it is known that PTSD patientsexhibit high levels of catecholamines (CA), even in the absence of stress, the neural mechanisms underlying this condition are not understood. The selective serotonin (5-HT) reuptake inhibitors (SSRIs), paroxetine and sertraline, are the only drugs approved by the FDA for PTSD treatment. However, the role of 5-HT in PTSD and its relationship with CA is unknown and difficult to study in the complex human nervous system (NS). C. elegans is suited to provide insights into the crosstalk between 5-TH and CA as its NS is simple,has a defined neural wiring diagram and conserved neurotransmitter systems. Moreover, C. elegans coordinates stress response by releasing tyramine (TA) and octopamine (OA), which are structural and functional counterparts of CA, the mammalian fight or flight hormones.We here studied parameters that, in C. elegans, depend on 5-HT such as egg laying, pharyngeal pumping and letargus. We exposed tdc-1 and tbh-1 null mutants (unable to synthetize TA and OA, respectively) to exogenous 5-HT. We found that these mutants are hypersensitive to 5-TH. Moreover, we observed a reduction in the pharyngeal pumping rate in tph-1 null mutants (unable to synthetize 5-HT), which is partially rescued in tph-1;tbh-1 double mutants.These results strongly suggest that 5-HT acts antagonistically to CA in C. elegans. These opposite actions could be conserved in mammals and explain the efficiency of SSRIs in PTSD treatment.We are now digging into the molecular and cellular underpinning of these antagonistic effects by analyzing mutants in serotonin receptors (many of them homologous to human 5-HT receptors). This study will widen the understanding of the mechanisms involved in neuronal regulation of stress response and could also provide new insights for PTDS treatment.