Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission

McCabe, Matthew P.; Cullen, Erin R; Barrows, Caitlynn M.; Shore, Amy N.; Tooke, Katherine I; Laprade, Kathryn A; Stafford, James M.; Weston, Matthew C.

doi:10.7554/elife.51440

Cited by 58 publications

(60 citation statements)

References 80 publications

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“…35,65 Indeed, the distinct functions of mTORC1 and mTORC2 in the postsynaptic and presynaptic sites, respectively, have been reported. 66 To conclude, our results indicate age-specific responses to IF and RAPA treatment. Both IF and RAPA altered glucose levels similarly in young and old animals.…”

Section: Figsupporting

confidence: 51%

Dietary and Pharmacological Interventions That Inhibit Mammalian Target of Rapamycin Activity Alter the Brain Expression Levels of Neurogenic and Glial Markers in an Age-and Treatment-Dependent Manner

Celebi-Birand

Ardıç

Karoglu-Eravsar

et al. 2020

Rejuvenation Research

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Intermittent fasting (IF) and its mimetic, rapamycin extend lifespan and healthspan through mechanisms that are not fully understood. We investigated different short-term durations of IF and rapamycin on cellular and molecular changes in the brains of young (6-10 months) and old (26-31 months) zebrafish. Interestingly, our results showed that IF significantly lowered glucose levels while increasing DCAMKL1 in both young and old animals. This proliferative effect of IF was supported by the upregulation of foxm1 transcript in old animals. Rapamycin did not change glucose levels in young and old animals but had differential effects depending on age. In young zebrafish, proliferating cell nuclear antigen and the LC3-II/LC3-I ratio was decreased, whereas glial fibrillary acidic protein and gephyrin were decreased in old animals. The changes in proliferative markers and a marker of autophagic flux suggest an age-dependent interplay between autophagy and cell proliferation. Additionally, changes in glia and inhibitory tone suggest a suppressive effect on neuroinflammation but may push the brain toward a more excitable state. Mammalian target of rapamycin (mTOR) activity in the brain following the IF and rapamycin treatment was differentially regulated by age. Interestingly, rapamycin inhibited mTOR more potently in young animals than IF. Principal component analysis supported our conclusion that the regulatory effects of IF and rapamycin were agespecific, since we observed different patterns in the expression levels and clustering of young and old animals. Taken together, our results suggest that even a short-term duration of IF and rapamycin have significant effects in the brain at young and old ages, and that these are age and treatment dependent.

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Section: Figsupporting

confidence: 51%

Dietary and Pharmacological Interventions That Inhibit Mammalian Target of Rapamycin Activity Alter the Brain Expression Levels of Neurogenic and Glial Markers in an Age-and Treatment-Dependent Manner

Celebi-Birand

Ardıç

Karoglu-Eravsar

et al. 2020

Rejuvenation Research

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“…However, the precise role of mTORC2 is yet to be elucidated. Several studies revealed that mTORC2 may be involved in myelination of oligodendrocyte [ 48 ] and glutamate synaptic transmission [ 49 ]. Prolonged, but not acute, treatment with rapamycin was reported to lead to interference with mTORC2 [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment

Kwon

Cho

et al. 2020

IJMS

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy.

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“…Although we did not pursue the entire interactome here, future studies investigating the interactions with members of the mTOR pathway and anaphase-promoting complex should be very fruitful. As we were preparing this work, a new study demonstrated that mTORC1 is involved in postsynaptic responses in hippocampal glutamatergic neurons, whereas mTORC2 modulates presynaptic release (McCabe et al, 2020). Given the importance of proteostasis at the synapse-and its failure in many neurological diseases (Zoghbi and Bear, 2012)-the close coordination of different protein-regulating activities is intuitively appealing.…”

Section: Implications Of the Interactomementioning

confidence: 99%

Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

Botta

Chemiakine

et al. 2021

Preprint

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The RNA-binding protein (RBP) Pumilio1 (PUM1) is associated with two distinct diseases: a late-onset ataxia and a neurodevelopmental syndrome. The ataxia patients retain 75% of normal PUM1 levels, the syndromic patients ~50%, but this seems inadequate to explain the difference in phenotypes. We hypothesized that mild disease results from dysregulation of PUM1 targets, whereas severe disease involves disruption of PUM1 complexes and deregulation of shared targets. We therefore developed a PUM1 interactome for the murine brain and found that PUM1 shares targets with several RBP interactors (PUM2, FMRP, AGO2, and RBFOX3). PUM1 haploinsufficiency destabilizes these RBPs to varying degrees by brain region and sex, and alters expression of their shared targets, but the milder disease-causing mutation affects only PUM1-specific targets. These data indicate that dosage-sensitive proteins can produce different phenotypes by different mechanisms, and that there may be more intimate cooperation among RBPs than expected.

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Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission

Cited by 58 publications

References 80 publications

Dietary and Pharmacological Interventions That Inhibit Mammalian Target of Rapamycin Activity Alter the Brain Expression Levels of Neurogenic and Glial Markers in an Age-and Treatment-Dependent Manner

Dietary and Pharmacological Interventions That Inhibit Mammalian Target of Rapamycin Activity Alter the Brain Expression Levels of Neurogenic and Glial Markers in an Age-and Treatment-Dependent Manner

REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment

Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

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