S179. ADMINISTRATION OF ROTENONE DURING NEONATAL PERIOD INDUCES SCHIZOPHRENIA-LIKE BEHAVIOR
Authors: Siena Amanda , Varga Thiago , Simões Juan , Henrique Elisandra , Camargo Ramos Aline , Rosenstock Tatiana 
Published: May 2020

Abstract

Background
The neurodevelopment refers to the process that generates and shapes the nervous system of animals. It begins during the earliest stages of embryonic development and it is the last system to be completed after birth, which occurs during the end of adolescence. The majority of mechanisms that constitutes neurodevelopment, such as cell proliferation, migration and neural differentiation, axon growth cone and dendritic filopodia formation as well as synapse are ATP dependents, therefore mitochondria dependents. Hence, disturbs during nervous system development can lead to behavioral deficits and neuropsychiatric disorders, such as schizophrenia. Results of our research group showed that a mitochondria dysfunction during neurodevelopment, by Rotenone (a complex I inhibitor) administration, induces behavioral deficits, such as hyperlocomotion and decreased social interaction, when the rats were young adults (60 days old). Thus, the objective of this study was to evaluate the behavioral deficits in an early age (prodromal phase) and if the behavioral deficits presented at young adulthood could be attenuated or reverted by antipsychotic (Haldol – Hal) or psychostimulant (Metilphenidate – MPD). Notwithstanding, draw a parallel between this animal model and a neuropsychiatric disorder.

Methods
To reach this goal, we treated intraperitoneally wistar puppies (P) with Rotenone 0.1mg/kg (Rot), Saline (Sal) or Vehicle (Veh) (DMSO) during P5-P11. To verify the prodromal phase, we performed behavioral tests (open field, social interaction and contextual fear conditioning) at P35. Therefore, in order to analyze the behavior during the young adulthood (P60), each animal previously treated with Sal, Veh or Rot was then treated intraperitoneally, 30 min before the behavioral tests (open field, social interaction and contextual fear conditioning), with either Saline (Sal-Sal, Veh-Sal, Rot-Sal), Hal (Sal-Hal, Veh-Hal, Rot-Hal) or MPD (Sal-MPD, Veh-MPD, Rot-MPD).

Results
Results showed mean±SEM (n=8 for each group) and analyzed by One-Way Anova and Duncan post-hoc compared to control group (Sal-Sal 100%). At P35, we verified: i) no significant changes in locomotor activity between Rot and Sal; ii) decrease in social interaction after treatment with Rot (68.40%±3.077; p&lt;0.05 in relation to Sal); iii) a reduction in freezing time in contextual fear conditioning task to Rot group (45.20±8.03; p&lt;0.05 when compared to Sal). At P60, we noticed i) an increase in locomotor activity after treatment with Rot-Sal (134.88%±3.95; p&lt;0.05 when compared to Sal-Sal) that was decreased by treatment with Rot-Hal (94.76%±15.74; p&lt;0.05 when compared to Rot-Sal), but not with Rot-MPD (compared to Rot-Sal); ii) a decrease in social interaction at P60 after treatment with Rot-Sal (68.35%±5.87; p&lt;0.05 when compared to Sal-Sal) that was reverted by treatment with Rot-Hal (100.80%±6.66; p&lt;0.05 when compared to Rot-Sal) and also with Rot-MPD (100.6%±6,89; p&lt;0.05 when compared to Rot-Sal); iii) in contextual fear conditioning the animals treated with Rot presented a decrease in freezing response (31.50%±7.36; p&lt;0.05 when compared to Sal-Sal) that was reverted by treatment with Rot-Hal (81.21%±16.65; p&lt;0.05 when compared to Rot-Sal).

Discussion
We concluded that neonatal treatment with Rot promote behavior deficits at young age (P35), such as deficit in social interaction and emotional memory; in young adulthood (P60) we also verified deficit in social interaction and emotional memory, in addition to hyperlocomotion, that are mostly reverted with treatment with Hal, but not with MPD. Altogether our data suggest a relationship between mitochondria inhibition during neurodevelopment leading to schizophrenia-like behavior.