Using mitochondrial respiration inhibitors to design a novel model of bipolar disorder-like phenotype with construct, face and predictive validity

O Damri,N Shemesh,S Asslih,N Kara,A Daraushe,S Natour,O Noori,G Las,H Einat,G Agam

doi:10.1038/s41398-021-01215-y

Abstract

We mimicked mild mitochondrial-distress robustly reported in bipolar-disorder (BD) by chronic exposure to uniquely low doses of inhibitors of mitochondrial-respiration complexes in vitro and in vivo. Exposure of the neuronal-originating SH-SY5Y cells to very low dose (10 pM) rotenone, a mitochondrial-respiration complex (Co)I inhibitor, for 72 or 96 h did not affect cell viability and reactive oxygen species (ROS) levels. Yet, it induced a dual effect on mitochondrial-respiration: overshooting statistically significant several-fold increase of most oxygen-consumption-rate (OCR) parameters vs. significantly decreased all OCR parameters, respectively. Chronic low doses of 3-nitropropionic acid (3-NP) (CoII inhibitor) did not induce long-lasting changes in the cells’ mitochondria-related parameters. Intraperitoneal administration of 0.75 mg/kg/day rotenone to male mice for 4 or 8 weeks did not affect spontaneous and motor activity, caused behaviors associated with mania and depression following 4 and 8 weeks, respectively, accompanied by relevant changes in mitochondrial basal OCR and in levels of mitochondrial-respiration proteins. Our model is among the very few BD-like animal models exhibiting construct (mild mitochondrial dysfunction), face (decreased/increased immobility time in the forced-swim test, increased/decreased consumption of sweet solution, increased/decreased time spent in the open arms of the elevated plus maze) and predictive (reversal of rotenone-induced behavioral changes by lithium treatment) validity. Our rotenone regime, employing doses that, to the best of our knowledge, have never been used before, differs from those inducing Parkinson’s-like models by not affecting ROS-levels and cell-viability in vitro nor motor activity in vivo.

Highlights

Mitochondrial dysfunction (MD) has become a wellestablished facet of the pathophysiology of neuropsychiatric [for reviews see refs. 1,2]
Here we show that exposure of human neuronal cells (SH-SY5Y) in vitro, and male mice, in vivo, to low rotenone doses (2.5-fold lower than the lowest used to induce Parkinson’s disease (PD)-like models and, to the best of our knowledge, never used before19) results in mania- and depression-associated characteristics in a doseXtime-dependent manner
Cultures were grown for 24 h, the medium was changed to that containing rotenone (10, 102, 103, 104 pM) or 3-nitropropionic acid (3-NP) (1, 10, 100, 1000 nM) dissolved in DMSO

Summary

Introduction

Mitochondrial dysfunction (MD) has become a wellestablished facet of the pathophysiology of neuropsychiatric [for reviews see refs. 1,2]. Mitochondrial dysfunction (MD) has become a wellestablished facet of the pathophysiology of neuropsychiatric [for reviews see refs. Findings include disturbances in mitochondrial enzymes, calcium signaling, and energy metabolism[2,3], corroborating with the postmitotic nature of neurons, their utmost metabolic (OxPhos), decreased energy production and a shift towards glucose metabolism[6]. Brain metabolic impairment appears more prominent in BD-I than in BD-II, Damri et al Translational Psychiatry (2021)11:123 suggesting a correlation between the severity of MD and the severity of the illness[7]. Bipolar patients often exhibit symptoms characterizing subjects with mitochondrial disorders[8]. Corroborating with these studies numerous reports demonstrate beneficial effects of mood-stabilizers on mitochondrial-function (MF)[9,10,11,12]. We have previously shown that treating mice with lithium upregulates MF-related genes in the frontal-cortex and the hippocampus[13]

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