Neuronal mTORC1 Is Required for Maintaining the Nonreactive State of Astrocytes

Zhang, Yue; Xu, Song; Liang, Kangyan; Li, Kai; Zou, Zhipeng; Cs, Yang; Tan, Kang Wei; Cao, Xiong; Jiang, Yu; Gao, Tianming; Bai, Xiaochun

doi:10.1074/jbc.m116.744482

Cited by 22 publications

(26 citation statements)

References 47 publications

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“…previously shown to suppress astrocyte activation (Kang et al, 2014;Y. Zhang et al, 2017), and our RNA-Seq results revealed that the FGF2 transcript was markedly increased in the hippocampus of FBN-ARO-KO1GCI mice versus FLOX1GCI mice.…”

Section: Depletion Of Forebrain Neuronal E2 Invokes Compromised Astrosupporting

confidence: 69%

“…RNA-Seq analysis showed increased FGF2 mRNA levels in FBN-ARO-KO mice after GCI, and double immunohistochemistry revealed that the FGF2 protein was significantly elevated in hippocampal neurons in FBN-ARO-KO mice after GCI. Neuron-derived FGF2 has been shown to exert an inhibitory effect on astrocyte activation by suppressing GFAP expression in astrocytes (Reilly et al, 1998;Y. Zhang et al, 2017).…”

Section: Role Of Neuronal Fgf2 In Neuron-derived E2-regulated Astrocymentioning

confidence: 99%

“…Zhang et al, 2017). Blocking the FGF2 receptor in astrocytes by immunoneutralization or conditional deletion invokes reactive astrogliosis basally, and strongly enhances it after injury (Kang et al, 2014;Y. Zhang et al, 2017), indicating that FGF2 is an important signal to restrain induction of reactive astrocytes.…”

Section: Role Of Neuronal Fgf2 In Neuron-derived E2-regulated Astrocymentioning

confidence: 99%

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Neuron-Derived Estrogen Is Critical for Astrocyte Activation and Neuroprotection of the Ischemic Brain

Sareddy²,

Wang

et al. 2020

J. Neurosci.

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17b-Estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but the functions of neuron-derived E2 in the ischemic brain are unclear. Here, we used a forebrain neuron-specific aromatase KO (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain and determine its roles after global cerebral ischemia. We demonstrated that ovariectomized female FBN-ARO-KO mice exhibited significantly attenuated astrocyte activation, astrocytic aromatization, and decreased hippocampal E2 levels compared with FLOX mice. Furthermore, FBN-ARO-KO mice had exacerbated neuronal damage and worse cognitive dysfunction after global cerebral ischemia. Similar results were observed in intact male mice. RNA-seq analysis revealed alterations in pathways and genes associated with astrocyte activation, neuroinflammation, and oxidative stress in FBN-ARO-KO mice. The compromised astrocyte activation in FBN-ARO-KO mice was associated with robust downregulation of the astrocyte-derived neurotrophic factors, BDNF and IGF-1, as well as the astrocytic glutamate transporter, GLT-1. Neuronal FGF2, which acts in a paracrine manner to suppress astrocyte activation, was increased in FBN-ARO-KO neurons. Interestingly, blocking FGF2 signaling by central injection of FGFR3neutralizing antibody was able to reverse the diminishment in neuroprotective astrocyte reactivity, and attenuate neuronal damage in FBN-ARO-KO mice. Moreover, in vivo E2 replacement suppressed FGF2 signaling and rescued the compromised reactive astrogliosis and cognitive deficits. Collectively, our data provide novel genetic evidence for a beneficial role of neuron-derived E2 in astrocyte activation, neuroprotection, and cognitive preservation following ischemic injury to the brain.

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Section: Depletion Of Forebrain Neuronal E2 Invokes Compromised Astrosupporting

confidence: 69%

Section: Role Of Neuronal Fgf2 In Neuron-derived E2-regulated Astrocymentioning

confidence: 99%

Section: Role Of Neuronal Fgf2 In Neuron-derived E2-regulated Astrocymentioning

confidence: 99%

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Neuron-Derived Estrogen Is Critical for Astrocyte Activation and Neuroprotection of the Ischemic Brain

Sareddy²,

Wang

et al. 2020

J. Neurosci.

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“…However, for neurons, it has already been shown that extent of mTOR hyperactivity correlates with seizure severity and associated neuropathology ( 73 ). Finally, in addition to intrinsic astrocytic properties, maintenance of a non-reactive state in astrocytes was also shown to depend on neuronal mTORC1 signaling, adding yet another level to altered astrocyte function in TSC ( 74 ).…”

Section: Astrocytesmentioning

confidence: 99%

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

et al. 2020

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Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

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“…5 A and B, compare bar 3 with 1). Suppression of mTORC1 not only disinhibits autophagy but also reduces protein translation, which may independently affect spine morphology and soma body size (35,38,39), and can potentially inhibit cell growth, proliferation, and ribosome biogenesis. To distinguish the contribution of auto- phagy to the rescue of spine morphology, we next delivered lentivirus carrying shRaptor to suppress mTORC1 together with shRNA directed to Atg7 (40)(41)(42), an E1-like ligase essential for autophagosome formation, directly into the CA1 of Fmr1-KO mice to selectively block autophagy (43).…”

Section: Activation Of Autophagy Ameliorates Aberrant Spine Morphologmentioning

confidence: 99%

Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice

Yan

Porch

Court-Vazquez

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

111

103

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Fragile X syndrome (FXS) is the most frequent form of heritable intellectual disability and autism. Fragile X (Fmr1-KO) mice exhibit aberrant dendritic spine structure, synaptic plasticity, and cognition. Autophagy is a catabolic process of programmed degradation and recycling of proteins and cellular components via the lysosomal pathway. However, a role for autophagy in the pathophysiology of FXS is, as yet, unclear. Here we show that autophagic flux, a functional readout of autophagy, and biochemical markers of autophagy are down-regulated in hippocampal neurons of fragile X mice. We further show that enhanced activity of mammalian target of rapamycin complex 1 (mTORC1) and translocation of Raptor, a defining component of mTORC1, to the lysosome are causally related to reduced autophagy. Activation of autophagy by delivery of shRNA to Raptor directly into the CA1 of living mice via the lentivirus expression system largely corrects aberrant spine structure, synaptic plasticity, and cognition in fragile X mice. Postsynaptic density protein (PSD-95) and activity-regulated cytoskeletal-associated protein (Arc/Arg3.1), proteins implicated in spine structure and synaptic plasticity, respectively, are elevated in neurons lacking fragile X mental retardation protein. Activation of autophagy corrects PSD-95 and Arc abundance, identifying a potential mechanism by which impaired autophagy is causally related to the fragile X phenotype and revealing a previously unappreciated role for autophagy in the synaptic and cognitive deficits associated with fragile X syndrome.

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Neuronal mTORC1 Is Required for Maintaining the Nonreactive State of Astrocytes

Cited by 22 publications

References 47 publications

Neuron-Derived Estrogen Is Critical for Astrocyte Activation and Neuroprotection of the Ischemic Brain

Neuron-Derived Estrogen Is Critical for Astrocyte Activation and Neuroprotection of the Ischemic Brain

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice

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