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

Hodges, Jennifer L.; Yu, Xinzhu; Gilmore, Anthony; Bennett, Hannah C.; Tjia, Michelle; Perna, James; Chen, Chia Chien; Li, Xiang; Ju, Lu; Zuo, Yi

doi:10.1016/j.biopsych.2016.08.036

Cited by 71 publications

(84 citation statements)

References 52 publications

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“…44,45 Selective suppression of FMRP in glial cells only—in this case, astrocytes—is sufficient to bring about a neural and behavioral phenotype evocative of FXS in mice. 46 There is likewise evidence that the population of oligodendrocyte precursor cells is reduced in Fmr1 knockout mice, and this reduction may contribute to subsequent myelin deficits arising during early postnatal development. 8 Moreover, FMRP is also necessary for regulating the growth and refinement of axons, 9,10 and axonal development absent of FMRP may induce dendritic spine dysmorphologic features.…”

Section: Discussionmentioning

confidence: 99%

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Swanson¹,

Wolff

Shen³

et al. 2018

JAMA Psychiatry

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IMPORTANCE Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. OBJECTIVE To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. DESIGN, SETTING, AND PARTICIPANTS Longitudinal behavioral and brain imaging data were collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. MAIN OUTCOMES AND MEASURES Nineteen major white matter pathways were defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. RESULTS There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate–corrected P = .03; right uncinate, F = 21.8; P = .004). CONCLUSIONS AND RELEVANCE The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.

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Section: Discussionmentioning

confidence: 99%

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Swanson¹,

Wolff

Shen³

et al. 2018

JAMA Psychiatry

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“…A recent study of human patients shows FMR1 epigenetic alterations silence FMRP specifically in neurons, but not glia or neurons obtained from reprogrammed pluripotent stem cells [13]. In the mouse FXS model, recent work shows FMRP loss changes cell differentiation kinetics for both neurons and glia (Table 1) [14], and astrocyte-specific FMRP knockout in mice increases neuronal dendritic spine density similar to the global FXS condition [15]. Within neurons in all model systems, the soma contains the vast majority of FMRP, yet the lion’s share of research and discussion focuses on local FMRP functions at the synapse [2,16–19].…”

Section: Overview Of Expanding Fmrp Functionsmentioning

confidence: 99%

“…Partnerships with other mRNA-binding proteins could provide the long-sought specificity for coupled control of transcript targets in neuron class-specific mechanisms [40–43]. FMRP roles in glia may also contribute to FXS [13–15], and this remains an important question. Intercellular glial-neuron signaling, as well as trans -synaptic signaling, may have central roles in FXS neuropathology, which are just coming to light [63–67].…”

Section: Part V: Future Directionsmentioning

confidence: 99%

Multifarious Functions of the Fragile X Mental Retardation Protein

2017

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Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder, results from loss of Fragile X Mental Retardation Protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of involvement in RNA-, channel- and protein-binding that modulates calcium signaling, activity-dependent critical period development and excitation-inhibition neural circuitry balance. This article contextualizes three years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles; to determine whether FMRP has a multitude of unrelated functions, or combinatorial mechanisms can explain its multifaceted existence.

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“…These features include macroorchidism (Bakker et al ., 1994), hyperactivity (per open field test; Kazdoba et al ., 2014; also Mineur et al ., 2002), attention deficits (Moon et al ., 2006), altered anxiety-related behaviors (Kazdoba et al ., 2014; Saré et al ., 2016), impaired social communication (Mineur et al ., 2006), sensory filtering deficits (Frankland et al ., 2004), motor deficits (Padmashri et al ., 2013; Hodges et al ., in press), and subtle cognitive impairments (Bakker et al ., 1994). Further studies have replicated Fmr1 -KO subtle cognitive impairments (in water maze reversal task; D’Hooge et al ., 1997; radial arm task Mineur et al ., 2002; in fear memory Zhao et al ., 2005, in five-choice serial reaction time test, Krueger et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

Bonasera

Chaudoin

Goulding

et al. 2017

Genes Brain and Behavior

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Fragile X syndrome (FXS) is a common inherited disorder that significantly impacts family and patient day-to-day living across the entire lifespan. The childhood and adolescent behavioral consequences of FXS are well-appreciated. However, there are significantly fewer studies (except those examining psychiatric comorbidities) assessing behavioral phenotypes seen in adults with FXS. Mice engineered with a genetic lesion of Fmr1 recapitulate important molecular and neuroanatomical characteristics of FXS, and provide a means to evaluate adult behavioral phenotypes associated with FXS. We give the first description of baseline behaviors including feeding, drinking, movement, and their circadian rhythms; all observed over 16 consecutive days following extensive environmental habituation in adult Fmr1-KO mutant mice. We find no genotypic changes in mouse food ingestion, feeding patterns, metabolism, or circadian patterns of movement, feeding, and drinking. After habituation, Fmr1-KO mice demonstrate significantly less daily movement during their active phase (the dark cycle). However, Fmr1-KO mice have more bouts of activity during the light cycle compared to wildtypes. In addition, Fmr1-KO mice demonstrate significantly less daily water ingestion during the circadian dark cycle, and this reduction in water intake is accompanied by a decrease in the amount of water ingested per lick. The observed water ingestion and circadian phenotypes noted in Fmr1-KO mice recapitulate known clinical aspects previously described in FXS. The finding of decreased movement in Fmr1-KO mice is novel, and suggests a dissociation between baseline and novelty-evoked activity for Fmr1-KO mice.

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

Cited by 71 publications

References 52 publications

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Multifarious Functions of the Fragile X Mental Retardation Protein

Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

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