Embryological exposure to valproic acid disrupts morphology of the deep cerebellar nuclei in a sexually dimorphic way

Mowery, Todd M.; Wilson, Sarah M.; Kostylev, Polina V.; Dina, Blair; Buchholz, Jennifer B.; Prieto, Anne L.; Garraghty, Preston E.

doi:10.1016/j.ijdevneu.2014.10.003

Cited by 26 publications

(16 citation statements)

References 92 publications

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“…VPA exposure leads to decreased thickness of the PFC and the basolateral amygdala at early ages, and of the hippocampal CA1 at all ages [332]. Other brain areas that are affected include the cerebellum which decreases in size [247], and the amygdala which increases in size [265]. …”

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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Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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“…Purkinje cell abnormalities were male-specific in the Reeler mouse model of ASD, and the Adnp mouse model of ASD shows sex-specific hippocampal gene expression, behavior alterations, and response to treatment [224,225]. The VPA mouse model shows complex patterns of sex specificity in androgen receptor expression and deep cerebellar nuclei morphology [226,227]. …”

Section: Multi-hit Hypothesis: (Epi)gene X Environment X Sex Interactmentioning

confidence: 99%

Sex Differences in Autism Spectrum Disorder: a Review

Ferri

Brodkin

2018

Curr Psychiatry Rep

282

181

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Recent work on the biological basis of the male preponderance of autism and other neurodevelopmental disorders includes discussion of a higher genetic burden in females and sex-specific gene mutations or epigenetic changes that differentially confer risk to males or protection to females. Other mechanisms discussed are sex chromosome and sex hormone involvement. Specifically, fetal testosterone is involved in many aspects of development and may interact with neurotransmitter, neuropeptide, or immune pathways to contribute to male vulnerability. Finally, the possibilities of female underdiagnosis and a multi-hit hypothesis are discussed. This review highlights current theories of male bias in developmental disorders. Topics include environmental, genetic, and epigenetic mechanisms; theories of sex chromosomes, hormones, neuroendocrine, and immune function; underdiagnosis of females; and a multi-hit hypothesis.

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“…[ 92 ] subsequently reported the selective overexpression of two subunits of the NMDA receptor and the commonly linked kinase calcium/calmodulin-dependent protein kinase II, indicating that VPA strongly stimulates NMDA receptor-mediated transmission and promotes plasticity in the neocortex. Mowery et al [ 93 ] also found higher cell counts in male than in female VPA rats, indicating a stronger but more aberrant local plastic reaction to VPA in males.…”

Section: Reviewmentioning

confidence: 99%

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism

et al. 2015

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Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event.

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Embryological exposure to valproic acid disrupts morphology of the deep cerebellar nuclei in a sexually dimorphic way

Cited by 26 publications

References 92 publications

Autism spectrum disorder: neuropathology and animal models

Autism spectrum disorder: neuropathology and animal models

Sex Differences in Autism Spectrum Disorder: a Review

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism

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