MTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse.

Emilio Garro-Martínez,Analía Bortolozzi,Esther Ruiz-Bronchal,Álvaro Díaz,Albert Adell,Eva Florensa-Zanuy,Fuencisla Pilar-Cuéllar,Maria Neus Fullana,Verónica Paz,Julia Senserrich,Elena Castro,Ángel Pazos

doi:10.3390/ijms22168671

Abstract

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.

Highlights

Given that brain brain-derived neurotrophic factor (BDNF) levels are critical in the neurobiology of Major depressive disorder (MDD), as well as in the antidepressant effects [45,46], we examined the BDNF expression in the intra-IL
The acute mammalian target of rapamycin (mTOR) downregulation in the IL cortex leads to reduced BDNF mRNA levels in medial prefrontal cortex (mPFC), together with impaired 5-HT and glutamate neurotransmission in the dorsal raphe nucleus (DRN), disturbances linked to neuropathophysiology of depression, as reported in preclinical [31,36,48,49] and clinical [50] studies
The present study demonstrates the causal link between mTOR expression in the infralimbic cortex and depressive-like state, with no clear implication in state anxiety-like behavior, at least in the open-field test

Summary

Introduction

One of the most relevant is the neurotrophic/neuroplastic hypothesis of depression, which postulates that a reduction in neurotrophic factors (such as the brain-derived neurotrophic factor, BDNF), in brain areas such as the hippocampus and the prefrontal cortex, underlies the neuronal atrophy associated with this disease in preclinical [2,3,4] and clinical studies [5,6]. Increased hippocampal BDNF levels were associated with antidepressant response in human studies [5], as well as in preclinical studies after chronic treatment with classic antidepressant drugs [7,8,9,10,11,12,13], or after acute treatment using fast-acting antidepressants such as ketamine [14,15,16,17,18]

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Conclusion