PMID- 34445375
OWN - NLM
STAT- MEDLINE
DCOM- 20210915
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 16
DP  - 2021 Aug 12
TI  - mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse.
LID - 10.3390/ijms22168671 [doi]
LID - 8671
AB  - 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.
FAU - Garro-Martinez, Emilio
AU  - Garro-Martinez E
AUID- ORCID: 0000-0001-8819-7503
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, 39011 
      Santander, Spain.
FAU - Fullana, Maria Neus
AU  - Fullana MN
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Department of Neuroscience and Experimental Therapeutics, Instituto de 
      Investigaciones Biomedicas de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain.
AD  - Systems Neuropharmacology Group, Instituto de Investigaciones Biomedicas August 
      Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
FAU - Florensa-Zanuy, Eva
AU  - Florensa-Zanuy E
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, 39011 
      Santander, Spain.
FAU - Senserrich, Julia
AU  - Senserrich J
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, 39011 
      Santander, Spain.
FAU - Paz, Veronica
AU  - Paz V
AUID- ORCID: 0000-0002-3225-7295
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Department of Neuroscience and Experimental Therapeutics, Instituto de 
      Investigaciones Biomedicas de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain.
AD  - Systems Neuropharmacology Group, Instituto de Investigaciones Biomedicas August 
      Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
FAU - Ruiz-Bronchal, Esther
AU  - Ruiz-Bronchal E
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Department of Neuroscience and Experimental Therapeutics, Instituto de 
      Investigaciones Biomedicas de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain.
AD  - Systems Neuropharmacology Group, Instituto de Investigaciones Biomedicas August 
      Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
FAU - Adell, Albert
AU  - Adell A
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
FAU - Castro, Elena
AU  - Castro E
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, 39011 
      Santander, Spain.
FAU - Diaz, Alvaro
AU  - Diaz A
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, 39011 
      Santander, Spain.
FAU - Pazos, Angel
AU  - Pazos A
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, 39011 
      Santander, Spain.
FAU - Bortolozzi, Analia
AU  - Bortolozzi A
AUID- ORCID: 0000-0002-2069-9192
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Department of Neuroscience and Experimental Therapeutics, Instituto de 
      Investigaciones Biomedicas de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain.
AD  - Systems Neuropharmacology Group, Instituto de Investigaciones Biomedicas August 
      Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
FAU - Pilar-Cuellar, Fuencisla
AU  - Pilar-Cuellar F
AUID- ORCID: 0000-0003-1229-001X
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Instituto de 
      Salud Carlos III, 28029 Madrid, Spain.
AD  - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC), Universidad de 
      Cantabria-CSIC-SODERCAN, 39011 Santander, Spain.
AD  - Departamento de Fisiologia y Farmacologia, Universidad de Cantabria, 39011 
      Santander, Spain.
LA  - eng
GR  - SAF2011-25020/Ministerio de Economia y Competitividad/
GR  - SAF2015-67457-R/Ministerio de Economia y Competitividad/
GR  - RTI2018-097534-B-I00/Ministerio de Ciencia, Innovacion y Universidades/
GR  - PID2019-105136RB-100/Ministerio de Ciencia e Innovacion/
GR  - PI19/00170/Instituto de Salud Carlos III/
GR  - CIBERSAM/Centro de Investigacion Biomedica en Red de Salud Mental/
PT  - Journal Article
DEP - 20210812
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Bdnf protein, mouse)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 333DO1RDJY (Serotonin)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - Depression/genetics/metabolism/*psychology
MH  - Disease Models, Animal
MH  - Dorsal Raphe Nucleus/metabolism
MH  - Gene Knockdown Techniques
MH  - Glutamic Acid/metabolism
MH  - Hindlimb Suspension
MH  - Male
MH  - Mice
MH  - Prefrontal Cortex/*metabolism
MH  - Serotonin/metabolism
MH  - Swimming
MH  - TOR Serine-Threonine Kinases/*genetics/*metabolism
PMC - PMC8395521
OTO - NOTNLM
OT  - BDNF
OT  - behavioral despair
OT  - infralimbic cortex
OT  - mTOR
OT  - neurotransmitter
COIS- The authors declare no conflict of interest.
EDAT- 2021/08/28 06:00
MHDA- 2021/09/16 06:00
PMCR- 2021/08/12
CRDT- 2021/08/27 01:24
PHST- 2021/07/14 00:00 [received]
PHST- 2021/08/08 00:00 [revised]
PHST- 2021/08/09 00:00 [accepted]
PHST- 2021/08/27 01:24 [entrez]
PHST- 2021/08/28 06:00 [pubmed]
PHST- 2021/09/16 06:00 [medline]
PHST- 2021/08/12 00:00 [pmc-release]
AID - ijms22168671 [pii]
AID - ijms-22-08671 [pii]
AID - 10.3390/ijms22168671 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Aug 12;22(16):8671. doi: 10.3390/ijms22168671.