Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice

Koehl, Muriel; Ladevèze, E.; Catania, Caterina; Cota, Daniela; Abrous, Djoher Nora

doi:10.1038/s41398-020-01187-5

Cited by 18 publications

(9 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like Tsc1/Tsc2 heterozygous knockouts, 4e-bp knockouts have lower thresholds for late long-term potentiation (LTP) [85]. Rps6k knockout mice display increased protein synthesis, cell division and smaller cell size while having deficiencies in learning and memory [86][87][88]. However, unlike 4e-bp knockouts, Rps6k knockouts show no differences in late-LTP.…”

Section: Mtor Hyperactivation Modelsmentioning

confidence: 99%

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Vasić

Jones

Haslinger

et al. 2021

Genes

View full text Add to dashboard Cite

Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.

show abstract

Section: Mtor Hyperactivation Modelsmentioning

confidence: 99%

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Vasić

Jones

Haslinger

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…Although it did not reach significance, a trend for an increase in the phosphorylation of ERK1/2 in the medial prefrontal cortex was noted. The phosphorylation of mTOR positively regulates the phosphorylation of the FMRP, the FMRP kinase S6K, and negatively regulates the activity of the FMRP phosphatase PP2Ac [ 33 , 34 , 35 ]. Thus, a transient decrease in the phosphorylation of mTOR may be a novel, non-canonical mechanism by which to induce translational events that induce long-lasting synaptic changes.…”

Section: Discussionmentioning

confidence: 99%

Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters

Borland

Dempsey

Peyla

et al. 2023

IJMS

View full text Add to dashboard Cite

Like many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions.

show abstract

“…The preference of the mice for sucrose-sweetened versus tap water was measured at 2 and 14 months of age as described by Koehl [ 33 ] with slight modifications. Mice were individually housed and acclimated to PhenoMaster system cages with food and water for two days.…”

Section: Methodsmentioning

confidence: 99%

Antidepressive-like Behavior-Related Metabolomic Signatures of Sigma-1 Receptor Knockout Mice

et al. 2022

View full text Add to dashboard Cite

Sigma-1 receptor (Sig1R) has been proposed as a therapeutic target for neurological, neurodegenerative, and psychiatric disorders, including depression and anxiety. Identifying metabolites that are affected by Sig1R absence and cross-referencing them with specific mood-related behaviors would be helpful for the development of new therapies for Sig1R-associated disorders. Here, we examined metabolic profiles in the blood and brains of male CD-1 background Sig1R knockout (KO) mice in adulthood and old age and correlated them with the assessment of depression- and anxiety-related behaviors. The most pronounced changes in the metabolic profile were observed in the plasma of adult Sig1R KO mice. In adult mice, the absence of Sig1R significantly influenced the amino acid, sphingolipid (sphingomyelin and ceramide (18:1)), and serotonin metabolic pathways. There were higher serotonin levels in plasma and brain tissue and higher histamine levels in the plasma of Sig1R KO mice than in their age-matched wild-type counterparts. This increase correlated with the reduced behavioral despair in the tail suspension test and lack of anhedonia in the sucrose preference test. Overall, these results suggest that Sig1R regulates behavior by altering serotonergic and histaminergic systems and the sphingolipid metabolic pathway.

show abstract

Inhibition of mTOR signaling by genetic removal of p70 S6 kinase 1 increases anxiety-like behavior in mice

Cited by 18 publications

References 78 publications

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Aggression Results in the Phosphorylation of ERK1/2 in the Nucleus Accumbens and the Dephosphorylation of mTOR in the Medial Prefrontal Cortex in Female Syrian Hamsters

Antidepressive-like Behavior-Related Metabolomic Signatures of Sigma-1 Receptor Knockout Mice

Contact Info

Product

Resources

About