<i>In Utero</i>Exposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation

Fujimura, Kimino; Mitsuhashi, Takayuki; Shibata, Shinsuke; Shimozato, Sachiko; Takahashi, Tsuyoshi

doi:10.1523/jneurosci.0229-16.2016

Cited by 42 publications

(41 citation statements)

References 52 publications

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“…Our imaging conditions could not distinguish whether this reflected a change in the number of neurons of each type, or a change in the level of expression of the fluorescent reporter. However, these changes are consistent with the function of VPA as a histone deacetylase inhibitor that affects the proliferative state of neural progenitor cells [65,66]. Expression of the glutamatergic neuron marker was reduced at the anterior-most region of the statoacoustic ganglion (as defined by a slight gap in neurod:GFP and isl2b:GFP transgene expression prior to the caudal-most part of the anterior lateral line ganglion).…”

Section: Discussionsupporting

confidence: 59%

Morphometric analysis and neuroanatomical mapping of the zebrafish brain

Gupta

Marquart

Horstick

et al. 2018

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Large-scale genomic studies have recently identified genetic variants causative for major neurodevelopmental disorders, such as intellectual disability and autism. However, determining how underlying developmental processes are affected by these mutations remains a significant challenge in the field. Zebrafish is an established model system in developmental neurogenetics that may be useful in uncovering the mechanisms of these mutations. Here we describe the use of voxel-intensity, deformation field, and volume-based morphometric techniques for the systematic and unbiased analysis of gene knock-down and environmental exposure-induced phenotypes in zebrafish. We first present a computational method for brain segmentation based on transgene expression patterns to create a comprehensive neuroanatomical map. This map allowed us to disclose statistically significant changes in brain microstructure and composition in neurodevelopmental models. We demonstrate the effectiveness of morphometric techniques in measuring changes in the relative size of neuroanatomical subdivisions in atoh7 morphant larvae and in identifying phenotypes in larvae treated with valproic acid, a chemical demonstrated to increase the risk of autism in humans. These tools enable rigorous evaluation of the effects of gene mutations and environmental exposures on neural development, providing an entry point for cellular and molecular analysis of basic developmental processes as well as neurodevelopmental and neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 59%

Morphometric analysis and neuroanatomical mapping of the zebrafish brain

Gupta

Marquart

Horstick

et al. 2018

Methods

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“… 108 Enlargement of the extra-axial fluid compartment suggests diminished uptake and flow of cerebrospinal fluid (CSF) with accumulation of brain metabolites (for example, β-amyloid and pro-inflamatory cytokines). 109 , 110 Increased extra-axial fluid volume in infancy has been linked to motor deficits 108 , 111 , 112 , 113 as well as over-proliferation of neuronal progenitor cells. 114 This latter observation led Lehtinen, Zappaterra 114 to suggest that CSF composition may have critical relevance to the pathogenesis of neurodevelopmental disorders and is consistent with the findings by Hazlett, Gu 56 suggesting early post-natal hyper-proliferation in autism.…”

Section: A Conceptual Framework For Early Brain and Behavior Developmmentioning

confidence: 99%

Toward a conceptual framework for early brain and behavior development in autism

2017

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Studies of infant siblings of older autistic probands, who are at elevated risk for autism, have demonstrated that the defining features of autism are not present in the first year of life but emerge late in the first and into the second year. A recent longitudinal neuroimaging study of high-risk siblings revealed a specific pattern of brain development in infants later diagnosed with autism, characterized by cortical surface area hyper-expansion in the first year followed by brain volume overgrowth in the second year that is associated with the emergence of autistic social deficits. Together with new observations from genetically defined autism risk alleles and rodent model, these findings suggest a conceptual framework for the early, post-natal development of autism. This framework postulates that an increase in the proliferation of neural progenitor cells and hyper-expansion of cortical surface area in the first year, occurring during a pre-symptomatic period characterized by disrupted sensorimotor and attentional experience, leads to altered experience-dependent neuronal development and decreased elimination of neuronal processes. This process is linked to brain volume overgrowth and disruption of the refinement of neural circuit connections and is associated with the emergence of autistic social deficits in the second year of life. A better understanding of the timing of developmental brain and behavior mechanisms in autism during infancy, a period which precedes the emergence of the defining features of this disorder, will likely have important implications for designing rational approaches to early intervention.

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“…Multiple effects of VPA on neural progenitor cell (NPC) proliferation and neuronal differentiation have been reported in primary cell cultures, including decreased NPC proliferation, increased neuronal differentiation, and inhibition of glial differentiation 47 . Long-term VPA exposure from embryonic day 1 until birth in mice increased the number of NPCs during the early-middle neurogenic period as well as postnatal neuronal production 48 . In contrast, we found thinner Ki67-positive EGL in cerebellum of VPA-exposed monkeys, indicative of fewer neuronal precursors.…”

Section: Discussionmentioning

confidence: 93%

Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates

et al. 2019

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Despite the substantial progress made in identifying genetic defects in autism spectrum disorder (ASD), the etiology for majority of ASD individuals remains elusive. Maternal exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug during pregnancy in human, has long been considered a risk factor to contribute to ASD susceptibility in offspring from epidemiological studies in humans. The similar exposures in murine models have provided tentative evidence to support the finding from human epidemiology. However, the apparent difference between rodent and human poses a significant challenge to extrapolate the findings from rodent models to humans. Here we report for the first time the neurodevelopmental and behavioral outcomes of maternal VPA exposure in non-human primates. Monkey offspring from the early maternal VPA exposure have significantly reduced NeuN-positive mature neurons in prefrontal cortex (PFC) and cerebellum and the Ki67-positive proliferating neuronal precursors in the cerebellar external granular layer, but increased GFAP-positive astrocytes in PFC. Transcriptome analyses revealed that maternal VPA exposure disrupted the expression of genes associated with neurodevelopment in embryonic brain in offspring. VPA-exposed juvenile offspring have variable presentations of impaired social interaction, pronounced stereotypies, and more attention on nonsocial stimuli by eye tracking analysis. Our findings in non-human primates provide the best evidence so far to support causal link between maternal VPA exposure and neurodevelopmental defects and ASD susceptibility in humans.

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In UteroExposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation

Cited by 42 publications

References 52 publications

Morphometric analysis and neuroanatomical mapping of the zebrafish brain

Morphometric analysis and neuroanatomical mapping of the zebrafish brain

Toward a conceptual framework for early brain and behavior development in autism

Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates

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