Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo

Nagaoka, Akira; Takehara, Hiroaki; Hayashi‐Takagi, Akiko; Noguchi, Junjirō; Ishii, Kotaro; Shirai, Fukutoshi; Yagishita, Sho; Akagı, Takanori; Ichikı, Takanori; Kasai, Hideaki

doi:10.1038/srep26651

Cited by 57 publications

(101 citation statements)

References 63 publications

(85 reference statements)

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“…Therefore, loss of Fmr1 function may alter spine turnover and motility without causing a detectable change in spine density within fixed mouse brain tissue. Consistent with this idea, in vivo two‐photon imaging revealed high spine turnover ratios on pyramidal neurons in various brain regions of Fmr1 knockout mice, including L5 and L2/3 of the barrel cortex and L5 of the motor and visual cortex, while overall spine density appeared to be largely unchanged compared to WT mice . Furthermore, Fmr1 knockout mice exhibited reduced sensitivity of spine turnover ratio in L5 pyramidal neurons to sensory experience and motor learning .…”

Section: Dendritic Spines In Neurodevelopmental Disorderssupporting

confidence: 54%

“…Consistent with this idea, in vivo two-photon imaging revealed high spine turnover ratios on pyramidal neurons in various brain regions of Fmr1 knockout mice, including L5 and L2/3 of the barrel cortex and L5 of the motor and visual cortex, while overall spine density appeared to be largely unchanged compared to WT mice. [86][87][88][89] Furthermore, Fmr1 knockout mice exhibited reduced sensitivity of spine turnover ratio in L5 pyramidal neurons to sensory experience and motor learning. 86,89 These results suggest that Fmr1 regulates spine dynamics and experience-dependent plasticity during development.…”

Section: Human Brain Pathologymentioning

confidence: 99%

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Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders

Nishiyama

2019

Psychiatry Clin Neurosci

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Dendritic spines are tiny postsynaptic protrusions from a dendrite that receive most of the excitatory synaptic input in the brain. Functional and structural changes in dendritic spines are critical for synaptic plasticity, a cellular model of learning and memory. Conversely, altered spine morphology and plasticity are common hallmarks of human neurodevelopmental disorders, such as intellectual disability and autism. The advances in molecular and optical techniques have allowed for exploration of dynamic changes in structure and signal transduction at single‐spine resolution, providing significant insights into the molecular regulation underlying spine structural plasticity. Here, I review recent findings on: how synaptic stimulation leads to diverse forms of spine structural plasticity; how the associated biochemical signals are initiated and transmitted into neuronal compartments; and how disruption of single genes associated with neurodevelopmental disorders can lead to abnormal spine structure in human and mouse brains. In particular, I discuss the functions of the Ras superfamily of small GTPases in spatiotemporal regulation of the actin cytoskeleton and protein synthesis in dendritic spines. Multiple lines of evidence implicate disrupted Ras signaling pathways in the spine structural abnormalities observed in neurodevelopmental disorders. Both deficient and excessive Ras activities lead to disrupted spine structure and deficits in learning and memory. Dysregulation of spine Ras signaling, therefore, may play a key role in the pathogenesis of multiple neurodevelopmental disorders with distinct etiologies.

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Section: Dendritic Spines In Neurodevelopmental Disorderssupporting

confidence: 54%

Section: Human Brain Pathologymentioning

confidence: 99%

Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders

Nishiyama

2019

Psychiatry Clin Neurosci

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“…Reduced neuronal plasticity of various cortical cell types is repeatedly reported in FMR1 knockout animals (for example, Li et al, 2002;Gocel et al, 2012;Padmashri et al, 2013;Yang et al, 2014;Koga et al, 2015;Martin et al, 2016;Nagaoka et al, 2016). FMRP is strongly expressed in almost all layers throughout the neocortex in mature brains.…”

Section: Cortex Layermentioning

confidence: 91%

Cellular distribution of the fragile X mental retardation protein in the mouse brain

Zorio

Jackson

Liu

et al. 2016

J of Comparative Neurology

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The fragile X mental retardation protein (FMRP) plays an important role in normal brain development. Absence of FMRP, caused by transcriptional silencing of FMR1 gene, results in abnormal neuronal morphologies in a selected manner throughout the brain and leads to intellectual deficits and sensory dysfunction in the fragile X syndrome (FXS). Despite the paramount importance of FMRP for proper brain function, its overall expression pattern in the mammalian brain at the resolution of individual neuronal cell groups is not known. In this study, we used FMR1 knockout and their isogenic wild type mice to systematically map the distribution of FMRP expression in the entire mouse brain. Using immunocytochemistry and cellular quantification analyses, we identified a large number of prominent cell groups expressing high levels of FMRP at the subcortical levels, in particular sensory and motor neurons in the brainstem and thalamus. In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels. More importantly, we describe differential patterns of FMRP distribution in both cortical and subcortical brain regions. Almost all major brain areas contain high and low levels of FMRP cell groups adjacent to each other or between layers of the same cortical areas. These differential patterns indicate that FMRP expression is specific to individual neuronal cell groups, instead of associated with brain regions as previously considered. Taken together, these findings support the notion that FMRP mechanisms of neuronal regulation are cell-type specific and strongly implicate the contribution of fundamental sensory and motor processing at subcortical levels to FXS pathology.

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“…Postnatal day 4–7 Fmr1 −/− mice show motility and turnover of spines comparable to WT mice in the somatosensory cortex [79], but the spine turnover rate increases in 10–12 day old mice [78] as well as in older Fmr1 −/− mice [118, 273, 353]. Spine turnover rate is also higher in the visual cortex of adult Fmr1 −/− mice [251]. …”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo

Cited by 57 publications

References 63 publications

Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders

Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders

Cellular distribution of the fragile X mental retardation protein in the mouse brain

Autism spectrum disorder: neuropathology and animal models

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