mTOR Knockdown in the Infralimbic Cortex Evokes A Depressive-like State in Mouse.
Emilio Garro-MartínezMaria Neus FullanaEva Florensa-ZanuyJulia SenserrichVerónica PazEsther Ruiz-BronchalAlbert AdellElena CastroÁlvaro DíazÁngel PazosAnalia BortolozziFuencisla Pilar-CuéllarPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- cell proliferation
- poor prognosis
- signaling pathway
- binding protein
- depressive symptoms
- emergency department
- functional connectivity
- spinal cord
- metabolic syndrome
- liver failure
- skeletal muscle
- drug delivery
- cell therapy
- intensive care unit
- small molecule
- mesenchymal stem cells
- bone marrow
- spinal cord injury
- high fat diet induced
- extracorporeal membrane oxygenation
- adverse drug
- adipose tissue
- acute respiratory distress syndrome
- protein protein
- hyaluronic acid
- endoplasmic reticulum stress