mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse
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, ca...
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doaj-f8369d7517564600b7f17f1a8d4f35fd2021-08-26T13:52:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-01228671867110.3390/ijms22168671mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in MouseEmilio Garro-Martínez0Maria Neus Fullana1Eva Florensa-Zanuy2Julia Senserrich3Verónica Paz4Esther Ruiz-Bronchal5Albert Adell6Elena Castro7Álvaro Díaz8Ángel Pazos9Analía Bortolozzi10Fuencisla Pilar-Cuéllar11Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, SpainFast 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.https://www.mdpi.com/1422-0067/22/16/8671mTORinfralimbic cortexbehavioral despairBDNFneurotransmitter |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Emilio Garro-Martínez Maria Neus Fullana Eva Florensa-Zanuy Julia Senserrich Verónica Paz Esther Ruiz-Bronchal Albert Adell Elena Castro Álvaro Díaz Ángel Pazos Analía Bortolozzi Fuencisla Pilar-Cuéllar |
spellingShingle |
Emilio Garro-Martínez Maria Neus Fullana Eva Florensa-Zanuy Julia Senserrich Verónica Paz Esther Ruiz-Bronchal Albert Adell Elena Castro Álvaro Díaz Ángel Pazos Analía Bortolozzi Fuencisla Pilar-Cuéllar mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse International Journal of Molecular Sciences mTOR infralimbic cortex behavioral despair BDNF neurotransmitter |
author_facet |
Emilio Garro-Martínez Maria Neus Fullana Eva Florensa-Zanuy Julia Senserrich Verónica Paz Esther Ruiz-Bronchal Albert Adell Elena Castro Álvaro Díaz Ángel Pazos Analía Bortolozzi Fuencisla Pilar-Cuéllar |
author_sort |
Emilio Garro-Martínez |
title |
mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse |
title_short |
mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse |
title_full |
mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse |
title_fullStr |
mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse |
title_full_unstemmed |
mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse |
title_sort |
mtor knockdown in the infralimbic cortex evokes a depressive-like state in mouse |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-08-01 |
description |
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. |
topic |
mTOR infralimbic cortex behavioral despair BDNF neurotransmitter |
url |
https://www.mdpi.com/1422-0067/22/16/8671 |
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