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Article

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

by
Emilio Garro-Martínez
1,2,3,†,
Maria Neus Fullana
1,4,5,
Eva Florensa-Zanuy
1,2,3,
Julia Senserrich
1,2,3,
Verónica Paz
1,4,5,
Esther Ruiz-Bronchal
1,4,5,
Albert Adell
1,2,
Elena Castro
1,2,3,
Álvaro Díaz
1,2,3,
Ángel Pazos
1,2,3,
Analía Bortolozzi
1,4,5 and
Fuencisla Pilar-Cuéllar
1,2,3,*
1
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, 28029 Madrid, Spain
2
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria-CSIC-SODERCAN, 39011 Santander, Spain
3
Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011 Santander, Spain
4
Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain
5
Systems Neuropharmacology Group, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
*
Author to whom correspondence should be addressed.
†
Present address: Emilio Garro-Martínez, Department of Integrative Medical Biology (IMB), Umeå Universitet, 901 87 Umeå, Sweden.
Int. J. Mol. Sci. 2021, 22(16), 8671; https://doi.org/10.3390/ijms22168671
Submission received: 14 July 2021 / Revised: 8 August 2021 / Accepted: 9 August 2021 / Published: 12 August 2021
(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models)
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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.
Keywords: mTOR; infralimbic cortex; behavioral despair; BDNF; neurotransmitter mTOR; infralimbic cortex; behavioral despair; BDNF; neurotransmitter
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MDPI and ACS Style

Garro-Martínez, E.; Fullana, M.N.; Florensa-Zanuy, E.; Senserrich, J.; Paz, V.; Ruiz-Bronchal, E.; Adell, A.; Castro, E.; Díaz, Á.; Pazos, Á.; et al. mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse. Int. J. Mol. Sci. 2021, 22, 8671. https://doi.org/10.3390/ijms22168671

AMA Style

Garro-Martínez E, Fullana MN, Florensa-Zanuy E, Senserrich J, Paz V, Ruiz-Bronchal E, Adell A, Castro E, Díaz Á, Pazos Á, et al. mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse. International Journal of Molecular Sciences. 2021; 22(16):8671. https://doi.org/10.3390/ijms22168671

Chicago/Turabian Style

Garro-Martínez, Emilio, Maria Neus Fullana, Eva Florensa-Zanuy, Julia Senserrich, Verónica Paz, Esther Ruiz-Bronchal, Albert Adell, Elena Castro, Álvaro Díaz, Ángel Pazos, and et al. 2021. "mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse" International Journal of Molecular Sciences 22, no. 16: 8671. https://doi.org/10.3390/ijms22168671

APA Style

Garro-Martínez, E., Fullana, M. N., Florensa-Zanuy, E., Senserrich, J., Paz, V., Ruiz-Bronchal, E., Adell, A., Castro, E., Díaz, Á., Pazos, Á., Bortolozzi, A., & Pilar-Cuéllar, F. (2021). mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse. International Journal of Molecular Sciences, 22(16), 8671. https://doi.org/10.3390/ijms22168671

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