Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience

Arroyo, Erica D.; Fiole, Daniel; Mantri, Shilpa S.; Huang, Claire Yu-Mei; Portera‐Cailliau, Carlos

doi:10.1523/jneurosci.1734-18.2018

Cited by 22 publications

(19 citation statements)

References 37 publications

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“…We found that closing the pore with CoQ 10 on P9 acutely induced changes in morphology and density of dendritic spines in Fmr1 KOs. Because Fmr1 KO spines are pathologically unresponsive to novel sensory stimuli in the early postnatal period, our findings indicated modulation of spine dynamics following closure of the mPTP, similar to the long‐term potentiation‐induced spinogenesis seen shortly after theta‐burst stimulation in the normally developing rodent hippocampus 72,73 . Importantly, blocking the pathological leak on P9 normalized Fmr1 KO dendritic spine density several weeks later.…”

Section: Discussionsupporting

confidence: 57%

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

Griffiths

Wang

et al. 2020

FASEB j.

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Fragile X syndrome (FXS) is the leading known inherited intellectual disability and the most common genetic cause of autism. The full mutation results in transcriptional silencing of the Fmr1 gene and loss of fragile X mental retardation protein (FMRP) expression. Defects in neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders. Thus, we explored the integrity of forebrain mitochondria in Fmr1 knockout mice during the peak of synaptogenesis. We found inefficient thermogenic respiration due to futile proton leak in Fmr1 KO mitochondria caused by coenzyme Q (CoQ) deficiency and an open cyclosporine‐sensitive channel. Repletion of mitochondrial CoQ within the Fmr1 KO forebrain closed the channel, blocked the pathological proton leak, restored rates of protein synthesis during synaptogenesis, and normalized the key phenotypic features later in life. The findings demonstrate that FMRP deficiency results in inefficient oxidative phosphorylation during the neurodevelopment and suggest that dysfunctional mitochondria may contribute to the FXS phenotype.

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Section: Discussionsupporting

confidence: 57%

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

Griffiths

Wang

et al. 2020

FASEB j.

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“…These neurodevelopmental changes may be the result of atypical experience-dependent responses at the earliest stages of life. For example, FXS mice exposed to novel sensory input in the second postnatal week did not show the same significant increases in spine density as seen in wild-type mice [95]. However, mice that were exposed to enriched environments for longer periods of time had improved behavioral and morphological features, including more mature spines [96].…”

Section: Main Textmentioning

confidence: 99%

White matter as a monitoring biomarker for neurodevelopmental disorder intervention studies

Swanson

Hazlett

2019

J Neurodevelop Disord

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BackgroundEarly intervention is a valuable tool to support the development of toddlers with neurodevelopmental disorders. With recent research advances in early identification that allow for pre-symptomatic detection of autism in infancy, scientists are looking forward to intervention during infancy. These advances may be supported by the identification of biologically based treatment and outcome measures that are sensitive and dimensional.Main body of abstractThe purpose of this review is to evaluate white matter neurodevelopment as a monitoring biomarker for early treatment of neurodevelopmental disorders. Fragile X syndrome (FXS) and autism spectrum disorder (ASD) as used as exemplars. White matter has unique neurobiology, including a prolonged period of dynamic development. This developmental pattern may make white matter especially responsive to treatment. White matter develops aberrantly in children with ASD and FXS. Histologic studies in rodents have provided targets for FXS pharmacological intervention. However, pharmaceutical clinical trials in humans failed to garner positive clinical results. In this article, we argue that the use of neurobiological monitoring biomarkers may overcome some of these limitations, as they are objective, not susceptible to placebo effects, and are dimensional in nature.Short conclusionAs the field moves towards earlier detection and early intervention for neurodevelopmental disorders, we encourage scientists to consider the advantages of using neurobiological features as monitoring biomarkers.

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“…Indeed, it is increasingly recognized that some of the neural phenotypes reported in animal models of FXS and autism spectrum disorder (ASD) may reflect compensatory mechanisms or differential developmental experiences 44 , 45 . For example, it is well established that early differences in sensory experience, social interactions and maternal rearing, can alter numerous neural properties throughout life 47 – 53 . As a result of decreased social interactions, young FMRP-deficient animals could in effect inhabit an impoverished sensory environment.…”

Section: Introductionmentioning

confidence: 99%

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits

Motanis

Buonomano

2020

Sci Rep

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fragile X syndrome is a neurodevelopmental disorder associated with a broad range of neural phenotypes. Interpreting these findings has proven challenging because some phenotypes may reflect compensatory mechanisms or normal forms of plasticity differentially engaged by experiential differences. To help minimize compensatory and experiential influences, we used an ex vivo approach to study network dynamics and plasticity of cortical microcircuits. in Fmr1 −/y circuits, the spatiotemporal structure of Up-states was less reproducible, suggesting alterations in the plasticity mechanisms governing network activity. chronic optical stimulation revealed normal homeostatic plasticity of Up-states, however, Fmr1 −/y circuits exhibited abnormal experience-dependent plasticity as they did not adapt to chronically presented temporal patterns in an interval-specific manner. These results, suggest that while homeostatic plasticity is normal, Fmr1 −/y circuits exhibit deficits in the ability to orchestrate multiple forms of synaptic plasticity and to adapt to sensory patterns in an experience-dependent manner-which is likely to contribute to learning deficits. Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disabilities, and reflects loss of function mutations in the RNA binding protein, Fragile X Mental Retardation Protein (FMRP) 1-4. Since the generation of the first mouse model of FXS 5 , a large number of neural phenotypes have been associated with the syndrome including: abnormalities in dendritic spine morphology and stabilization 6-12 , altered shortand long-term forms of synaptic plasticity 13-20 , abnormal axonal development 19,21,22 , changes in interneuronal connectivity 23,24 , channelopathies 16,25-31 , and imbalanced excitation/inhibition 24,32-44. The sheer diversity of reported neural phenotypes highlights the challenge in determining which phenotypes are a primary consequence of the absence of FMRP, from those that reflect indirect secondary neural phenotypes. These secondary neural phenotypes could reflect: (1) compensatory and homeostatic mechanisms, i.e., genetic redundancy and homeostatic plasticity engaged to compensate for the primary consequences of the lack of FMRP 44-46 ; or (2) normal forms of plasticity shaped by experiential differences, including differences in sensory exploration, social interactions and maternal care. Indeed, it is increasingly recognized that some of the neural phenotypes reported in animal models of FXS and autism spectrum disorder (ASD) may reflect compensatory mechanisms or differential developmental experiences 44,45. For example, it is well established that early differences in sensory experience, social interactions and maternal rearing, can alter numerous neural properties throughout life 47-53. As a result of decreased social interactions, young FMRP-deficient animals could in effect inhabit an impoverished sensory environment. Indeed, it is also well established that in mouse models of FXS and ASD, animals experience differences in so...

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Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience

Cited by 22 publications

References 37 publications

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

White matter as a monitoring biomarker for neurodevelopmental disorder intervention studies

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits

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