Persistent astrocyte activation in the fragile <scp>X</scp> mouse cerebellum

Pacey, Laura; Guan, Sihui; Tharmalingam, Sujeenthar; Thomsen, C.; Hampson, David R.

doi:10.1002/brb3.400

Cited by 34 publications

(27 citation statements)

References 51 publications

(115 reference statements)

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“…Here, we observed that Fmr1 KO mice exhibited prominent GFAP expression, while in vitro astrocyte cultures displayed hypertrophy and increased GFAP levels, all of which are hallmark features of reactive astrogliosis. In support of our findings, separate studies have provided evidence for astrocytic activation in the cerebellum of Fmr1 KO mouse [66,67] and in patients with autism [65,72]. Zamanian et al conducted an extensive analysis on the genomic profile of reactive astrocytes, where they identified numerous genes of different signaling pathways were significantly induced [73].…”

Section: Discussionsupporting

confidence: 83%

“…With regards to FXS, microglia can directly mediate dendritic spine elimination via the complement system where excessive synapses are tagged with complement proteins (C1q and C3) and consequently engulfed by microglial cells expressing complement receptors [24,62,63]. There is clinical evidence suggesting excessive microglial activation in multiple brains regions of patients with ASD [64,65], but other studies did not detect any microglial activation or altered cytokine production in the Fmr1 KO mice [66,67]. In our study, we found a slight reduction in the number of Iba1-positive cells across the neocortex of Fmr1 KO mutants, further justifying the absence of microglial activation.…”

Section: Discussionmentioning

confidence: 99%

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Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

Lee

Lai

et al. 2019

Mol Brain

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Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the FMR1 gene and subsequent loss of its protein product, fragile X retardation protein (FMRP). One of the most robust neuropathological findings in post-mortem human FXS and Fmr1 KO mice is the abnormal increase in dendritic spine densities, with the majority of spines showing an elongated immature morphology. However, the exact mechanisms of how FMRP can regulate dendritic spine development are still unclear. Abnormal dendritic spines can result from disturbances of multiple factors during neurodevelopment, such as alterations in neuron numbers, position and glial cells. In this study, we undertook a comprehensive histological analysis of the cerebral cortex in Fmr1 KO mice. They displayed significantly fewer neuron and PV-interneuron numbers, along with altered cortical lamination patterns. In terms of glial cells, Fmr1 KO mice exhibited an increase in Olig2-oligodendrocytes, which corresponded to the abnormally higher myelin expression in the corpus callosum. Iba1-microglia were significantly reduced but GFAP-astrocyte numbers and intensity were elevated. Using primary astrocytes derived from KO mice, we further demonstrated the presence of astrogliosis characterized by an increase in GFAP expression and astrocyte hypertrophy. Our findings provide important information on the cortical architecture of Fmr1 KO mice, and insights towards possible mechanisms associated with FXS.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

Lee

Lai

et al. 2019

Mol Brain

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“…Moreover, we found that the level of glial fibrillary acidic protein (GFAP) is increased at 4 weeks when FMRP is depleted. Increased astrocyte differentiation was also reported from adult neural stem cells and hESCs and GFAP is upregulated in human and mouse postnatal brain . As astrocytes are involved in the developing synapse and in the abnormal dendritic arbors of Fmr1 ‐KO mice , we suggest that the increase of GFAP during early steps of neurogenesis contribute to the neuronal alterations observed in FXS.…”

Section: Discussionsupporting

confidence: 63%

Depletion of the Fragile X Mental Retardation Protein in Embryonic Stem Cells Alters the Kinetics of Neurogenesis

et al. 2016

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Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs). Repressing FMRP in ESCs increased the expression of amyloid precursor protein (APP) and Ascl1. When inducing neuronal differentiation, βIII-tubulin, p27 , NeuN, and NeuroD1 were upregulated, leading to an accelerated neuronal differentiation that was partially compensated at later stages. Interestingly, we observed that neurogenesis is also accelerated in the embryonic brain of Fmr1-knockout mice, indicating that our cellular model recapitulates the molecular alterations present in vivo. Importantly, we rescued the main phenotype of the Fmr1 knockdown cell line, not only by reintroducing FMRP but also by pharmacologically targeting APP processing, showing the role of this protein in the pathophysiology of FXS during the earliest steps of neurogenesis. Our work allows to define an early therapeutic window but also to identify more effective molecules for treating this disorder. Stem Cells 2017;35:374-385.

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“…One group reports no astrogliosis seen in post-mortem brains of persons with FXS (41). On the other hand, an elevated number of activated astrocytes was observed in the cerebellum of Fmr1 KO mice (42). Our results show no gross changes in the volume or reactivity of cortical astrocytes, but we can not exclude subtle changes to the fine astrocyte processes or alterations in astrocytic signaling exist.…”

Section: Discussionmentioning

confidence: 99%

Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome

Hodges

Gilmore

et al. 2017

Biological Psychiatry

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BACKGROUND Fragile X Syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, Fragile X Mental Retardation Protein (FMRP). Fmr1 global knock out (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS. METHODS Taking advantage of the Cre-lox system, we generated and characterized mice in which FMRP is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects. RESULTS We found that adult astrocyte-specific Fmr1 KO mice displayed an increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. While spine density was normal at one month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, expression of FMRP only in astrocytes was insufficient to rescue most spine or behavioral defects. CONCLUSIONS Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice.

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Persistent astrocyte activation in the fragile X mouse cerebellum

Cited by 34 publications

References 51 publications

Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

Depletion of the Fragile X Mental Retardation Protein in Embryonic Stem Cells Alters the Kinetics of Neurogenesis

Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome

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