Overproduction of Upper-Layer Neurons in the Neocortex Leads to Autism-like Features in Mice

Fang, Wei; Chen, Weiwei; Jiang, Liwen; Liu, Kai; Yung, Wing‐Ho; Fu, Amy Kit Yu; Ip, Nancy Y.

doi:10.1016/j.celrep.2014.11.003

Cited by 97 publications

(96 citation statements)

References 21 publications

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“…Several differences in white matter micro-structure may yield this combination of diffusion values, including increased myelination, increased axonal density, smaller axonal calibers, and/or increased extra-cellular matrix density (Mori and Zhang 2006). Numerous postmortem (Courchesne and Pierce 2005; Courchesne, Mouton, et al 2011; Santos et al 2011; Stoner et al 2014), genetic (Pinto et al 2010; Chow et al 2012; Bernier et al 2014; Sugathan et al 2014; Pramparo et al 2015), animal model (Fang et al 2014; Le Belle et al 2014; Orosco et al 2014; Sabers et al 2014), and cellular (Marchetto et al 2016; Packer 2016) studies suggest that, in many cases, autism is associated with a prenatal excess of neural proliferation, which would predict an excess of corresponding axons. While postmortem studies with toddlers have not examined axonal characteristics or reported axon numbers in the white matter of toddlers with autism, adults with autism do exhibit an abnormally large number of smaller caliber axons in frontal lobe areas (Zikopoulos and Barbas 2010).…”

Section: Discussionmentioning

confidence: 99%

Toddlers later diagnosed with autism exhibit multiple structural abnormalities in temporal corpus callosum fibers

Fingher

Dinstein

Ben-Shachar

et al. 2017

Cortex

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Interhemispheric functional connectivity abnormalities are often reported in autism and it is thus not surprising that structural defects of the corpus callosum (CC) are consistently found using both traditional MRI and DTI techniques. Past DTI studies however, have subdivided the CC into 2 or 3 segments without regard for where fibers may project to within the cortex, thus placing limitations on our ability to understand the nature, timing and neurobehavioral impact of early CC abnormalities in autism. Leveraging a unique cohort of 97 toddlers (68 autism; 29 typical) we utilized a novel technique that identified seven CC tracts according to their cortical projections. Results revealed that younger (<2.5 years old), but not older toddlers with autism exhibited abnormally low mean, radial, and axial diffusivity values in the CC tracts connecting the occipital lobes and the temporal lobes. Fractional anisotropy and the cross sectional area of the temporal CC tract were significantly larger in young toddlers with autism. These findings indicate that water diffusion is more restricted and unidirectional in the temporal CC tract of young toddlers who develop autism. Such results may be explained by a potential overabundance of small caliber axons generated by excessive prenatal neural proliferation as proposed by previous genetic, animal model, and postmortem studies of autism. Furthermore, early diffusion measures in the temporal CC tract of the young toddlers were correlated with outcome measures of autism severity at later ages. These findings regarding the potential nature, timing, and location of early CC abnormalities in autism add to accumulating evidence, which suggests that altered inter-hemispheric connectivity, particularly across the temporal lobes, is a hallmark of the disorder.

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Section: Discussionmentioning

confidence: 99%

Toddlers later diagnosed with autism exhibit multiple structural abnormalities in temporal corpus callosum fibers

Fingher

Dinstein

Ben-Shachar

et al. 2017

Cortex

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“…VPA has many targets, but one of its better characterized effects is the stimulation of the canonical Wnt signaling pathway through modulation of histone deacetylase and GSK3 [110–114], demonstrating that abnormal Wnt signaling likely plays an important role in the pathogenicity of VPA. A second model that was recently developed and more specifically implicates Wnt signaling is exposure of pregnant mice to the compound, XAV939, which is a tankyrase inhibitor, resulting in enhanced canonical Wnt signaling [115]. This leads to the expansion of the intermediate progenitor cell population in the developing cerebral cortex.…”

Section: Reviewmentioning

confidence: 99%

“…These mice exhibit ASD-like behavioral abnormalities, implicating that changes to canonical Wnt signaling during prenatal brain development can have a profound impact on brain size and function. These results suggest a causal relationship between abnormal modulation of Wnt signaling during neurodevelopment and autism-like features [115]. …”

Section: Reviewmentioning

confidence: 99%

Wnt signaling networks in autism spectrum disorder and intellectual disability

Kwan

Unda

Singh

2016

J Neurodevelop Disord

109

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BackgroundGenetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations).AbstractGiven the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.ConclusionsWe will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology.

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“…Over-proliferation of cortical progenitor cells may impact other mechanisms of post-natal development (e.g., dendritic arborization and decreased pruning 22 ). Fan et al 23 showed that overproduction of upper-layer neurons in the neocortex was associated with autism-like features in mice, and the 16p11.2 deletion mouse has been shown to exhibit altered cortical progenitor proliferation 24 . Furthermore, an imaging study described increased brain volume in individuals with a 16p11 deletion, a genetically-defined subgroup of individuals often presenting with ‘syndromic autism’ 15 .…”

mentioning

confidence: 99%

Early brain development in infants at high risk for autism spectrum disorder

Hazlett¹,

Gu²,

Munsell

et al. 2017

Nature

846

634

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Summary Brain enlargement has been observed in children with Autism Spectrum Disorder (ASD), but the timing of this phenomenon and its relationship to the appearance of behavioral symptoms is unknown. Retrospective head circumference and longitudinal brain volume studies of 2 year olds followed up at age 4 years, have provided evidence that increased brain volume may emerge early in development.1, 2 Studies of infants at high familial risk for autism can provide insight into the early development of autism and have found that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life3,4. These observations suggest that prospective brain imaging studies of infants at high familial risk for ASD might identify early post-natal changes in brain volume occurring before the emergence of an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that cortical surface area hyper-expansion between 6-12 months of age precedes brain volume overgrowth observed between 12-24 months in the 15 high-risk infants diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep learning algorithm primarily using surface area information from brain MRI at 6 and 12 months of age predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81%, sensitivity of 88%). These findings demonstrate that early brain changes unfold during the period in which autistic behaviors are first emerging.

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Overproduction of Upper-Layer Neurons in the Neocortex Leads to Autism-like Features in Mice

Cited by 97 publications

References 21 publications

Toddlers later diagnosed with autism exhibit multiple structural abnormalities in temporal corpus callosum fibers

Toddlers later diagnosed with autism exhibit multiple structural abnormalities in temporal corpus callosum fibers

Wnt signaling networks in autism spectrum disorder and intellectual disability

Early brain development in infants at high risk for autism spectrum disorder

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