Presynaptic<i>Fmr1</i>Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Hanson, Jesse E.; Madison, Daniel V.

doi:10.1523/jneurosci.4717-06.2007

Cited by 91 publications

(93 citation statements)

References 41 publications

(38 reference statements)

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“…Taken together, our results suggest that the neuroanatomic abnormalities of FXS are not laid out simultaneously but rather occur at different times in different regions, consistent with patterns of cortical development (8) and site-specific activity of FMRP (9,(19)(20)(21), likely representing a combination of pre-and postnatal processes. As such, it may be possible to track the efficacy of interventional strategies, such as metabotropic glutamate receptor antagonists (22), over time and in specific brain structures, with an understanding of the expected neurodevelopmental course in those structures.…”

Section: Discussionsupporting

confidence: 68%

Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome

Hoeft

Carter

Lightbody

et al. 2010

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

118

106

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Longitudinal neuroimaging investigation of fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, provides an opportunity to study the influence of a specific genetic factor on neurodevelopment in the living human brain. We examined voxel-wise gray and white matter volumes (GMV, WMV) over a 2-year period in 1-to 3-year-old boys with FXS (n = 41) and compared these findings to age-and developmentally matched controls (n = 28). We found enlarged GMV in the caudate, thalamus, and fusiform gyri and reduced GMV in the cerebellar vermis in FXS at both timepoints, suggesting early, possibly prenatal, genetically mediated alterations in neurodevelopment. In contrast, regions in which initial GMV was similar, followed by an altered growth trajectory leading to increased size in FXS, such as the orbital gyri, basal forebrain, and thalamus, suggests delayed or otherwise disrupted synaptic pruning occurring postnatally. WMV of striatal-prefrontal regions was greater in FXS compared with controls, and group differences became more exaggerated over time, indicating the possibility that such WM abnormalities are the result of primary FMRP-deficiency-related axonal pathology, as opposed to secondary connectional dysregulation between morphologically atypical brain structures. Our results indicate that structural abnormalities of different brain regions in FXS evolve differently over time reflecting time-dependent effects of FMRP deficiency and provide insight into their neuropathologic underpinnings. The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can "rescue" the FXS phenotype in affected individuals.F ragile X syndrome (FXS) is the most common cause of inherited intellectual disability. The condition is caused by expansion of the CGG repeat in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene, resulting in hypermethylation, transcriptional silencing, and reduction or loss of the gene product, the fragile X mental retardation protein (FMRP) (1). Loss of FMRP disrupts dendritic maturation, synaptic plasticity, and cerebral development (2). Although much is understood about the typical pattern of cerebral abnormality in adults and older children with FXS, relatively little is known about the evolving nature of these abnormalities in early childhood. One of the most consistent observations in FXS is enlargement of the caudate nucleus, which has been noted in children as young as 18 months (3), relative to both typically developing children and those with idiopathic developmental delay (4). Increased caudate size also shows a negative correlation with FMRP, indicating a genetic dose-response relationship (4, 5). Another consistent finding is reduced size of the cerebellar vermis, which has been observed in FXS across a wide range of ages (4-7). Vermis size has been shown to be positively correlated with FMRP (5), although in our recent study w...

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Section: Discussionsupporting

confidence: 68%

Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome

Hoeft

Carter

Lightbody

et al. 2010

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

118

106

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“…Findings from other groups also indicate lower connection probabilities in Fmr1 ko mice based on studies in a variety of systems, including cultured hippocampal neurons (Braun and Segal, 2000;Antar et al, 2006;Hanson and Madison, 2007) and climbing fiber to Purkinje cell synapses (Koekkoek et al, 2005). A recent study suggests a presynaptic role of FMRP (Hanson and Madison, 2007).…”

Section: Multiple Mechanistically Independent Defects In the L43 L3 mentioning

confidence: 91%

“…A recent study suggests a presynaptic role of FMRP (Hanson and Madison, 2007). In contrast, acute expression of FMRP in hippocampal neurons from Fmr1 ko mice reduced excitatory transmission from the postsynaptic site through a decrease of the number of synaptic contacts per connection (Pfeiffer and Huber, 2007).…”

Section: Multiple Mechanistically Independent Defects In the L43 L3 mentioning

confidence: 94%

Circuit and Plasticity Defects in the Developing Somatosensory Cortex ofFmr1Knock-Out Mice

Bureau¹,

Shepherd²,

Svoboda³

2008

J. Neurosci.

183

202

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Silencing of the Fmr1 gene causes fragile X syndrome. Although defects in synaptic plasticity in the cerebral cortex have been linked to cognitive impairments in Fmr1 knock-out (ko) mice, the specific cortical circuits affected in the syndrome are unknown. Here, we investigated the development of excitatory projections in the barrel cortex of Fmr1 ko mice. In 2-week-old Fmr1 ko mice, a major ascending projection connecting layer 4 (L4) to L3 (L43 L3), was defective in multiple and independent ways: its strength was reduced, caused by a lower connection probability; the axonal arbors of L4 cells were spatially diffuse in L2/3; the L43 L3 projection did not show experience-dependent plasticity. By 3 weeks, the strength of the L43 L3 projection was similar to that of wild type. Our data indicate that Fmr1 shapes sensory cortical circuits during a developmental critical period.

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“…Electrophysiology studies have previously showed that Fmr1 knockout neurons are less successful than wild-type neurons in forming functional excitatory synapses (Hanson and Madison, 2007). It has recently been speculated that activity-dependent local protein synthesis necessary for synaptic plasticity may also occur proximal to GABAergic synapses (Mackie and Katona, 2009).…”

Section: Conclusion and Clinical Significancementioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Cited by 91 publications

References 41 publications

Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome

Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome

Circuit and Plasticity Defects in the Developing Somatosensory Cortex ofFmr1Knock-Out Mice

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

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