Elevated microRNA-181c and microRNA-30d levels in the enlarged amygdala of the valproic acid rat model of autism

Loohuis, Nikkie F.M. Olde; Kole, Koen; Glennon, Jeffrey; Karel, Peter; Borg, G. Van der; Gemert, Y. van; Bosch, D. Van den; Meinhardt, Julia; Kos, Aron; Shahabipour, Fahimeh; Tiesinga, Paul; Bokhoven, Hans van; Martens, Gerard J.M.; Kaplan, Barry B.; Homberg, Judith R.; Aschrafi, Armaz

doi:10.1016/j.nbd.2015.05.006

Cited by 44 publications

(38 citation statements)

References 74 publications

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“…Furthermore, IL‐17a, produced by T helper 17 cells, was found to act downstream of IL‐6, leading to abnormal cortical development and behavioral phenotypes in MIA offspring 15. Previous studies examined miRNA levels in the embryonic or adult brain of ASD mice 32, 33. It should be noted that this is the first study to analyze the whole‐brain expression of ASD‐associated mRNAs and miRNAs at the transcriptome level, particularly in the early postnatal mouse brain, which is the main strength of this study.…”

Section: Discussionmentioning

confidence: 99%

Maternal immune activation alters brain microRNA expression in mouse offspring

Sunwoo

Jeon²,

Moon

et al. 2018

Ann Clin Transl Neurol

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ObjectiveMaternal immune activation (MIA) is associated with an increased risk of autism spectrum disorder (ASD) in offspring. Herein, we investigate the altered expression of microRNAs (miRNA), and that of their target genes, in the brains of MIA mouse offspring.MethodsTo generate MIA model mice, pregnant mice were injected with polyriboinosinic:polyribocytidylic acid on embryonic day 12.5. We performed miRNA microarray and mRNA sequencing in order to determine the differential expression of miRNA and mRNA between MIA mice and controls, at 3 weeks of age. We further identified predicted target genes of dysregulated miRNAs, and miRNA‐target interactions, based on the inverse correlation of their expression levels.ResultsMice prenatally subjected to MIA exhibited behavioral abnormalities typical of ASD, such as a lack of preference for social novelty and reduced prepulse inhibition. We found 29 differentially expressed miRNAs (8 upregulated and 21 downregulated) and 758 differentially expressed mRNAs (542 upregulated and 216 downregulated) in MIA offspring compared to controls. Based on expression levels of the predicted target genes, 18 downregulated miRNAs (340 target genes) and three upregulated miRNAs (60 target genes) were found to be significantly enriched among the differentially expressed genes. miRNA and target gene interactions were most significant between mmu‐miR‐466i‐3p and Hfm1 (ATP‐dependent DNA helicase homolog), and between mmu‐miR‐877‐3p and Aqp6 (aquaporin 6).InterpretationOur results provide novel information regarding miRNA expression changes and their putative targets in the early postnatal period of brain development. Further studies will be needed to evaluate potential pathogenic roles of the dysregulated miRNAs.

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Section: Discussionmentioning

confidence: 99%

Maternal immune activation alters brain microRNA expression in mouse offspring

Sunwoo

Jeon²,

Moon

et al. 2018

Ann Clin Transl Neurol

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“…The expression of the blots was densitometrically quantified, and the data after being normalized with NF-L or β-actin blots were expressed as mean ± SEM (n = 6). *p < 0.05, **p < 0.01 versus the sham + NC group, #p < 0.05 versus 2-VO + NC group Moreover, miR-181c is involved in many diseases of the nervous system, such as AD, epilepsy, multiple sclerosis (MS), autism, as well as glioblastoma with upregulation or downregulation [5,[32][33][34][35]. MiR-181c is known to be downregulated with aging in the human brain and targets age-related gene such as bromodomain PHD finger transcription factor (BPTF) [36].…”

Section: Discussionmentioning

confidence: 99%

“…miR-181c, one of the miR-181 family members, is widely expressed in the nervous system, especially in the hippocampus and the cortex [3,4]. In sponge-miR-181c infected neurons, an enrichment of genes involved in cellular assembly and modification, dendritic growth and branching, cell morphology, cellular growth, and proliferation are found by IPA gene ontology (GO) analysis [5]. According to the prediction of microRNA target gene, tripartite motif 2 (TRIM2) is one of the potential downstream targets of miR-181c [6].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Chen

Min

et al. 2016

Mol Neurobiol

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Chronic cerebral hypoperfusion (CCH) characterized by global cerebral ischemia is an important risk factor contributing to the development of dementia. MicroRNAs (miRNAs) play important roles in the cellular adaptation to long-term ischemia/hypoxia by turning off or on the expression of target genes. MiR-181c is widely expressed in the nervous system, and tripartite motif 2 (TRIM2) is one of its target genes. In this work, we had identified that progressive spatial memory deficiency was induced in the bilateral common carotid artery occlusion (2-VO) rat models. Meanwhile, inhibition of miR-181c expression and upregulation of TRIM2 in the hippocampus of 2-VO rats were found accompanying with reduction in the dendritic branching and dendrite spine density of the hippocampal neurons. Viral vector-mediated miR-181c delivery might improve the cognitive deficiency via TRIM2 on neurofilament light (NF-L) ubiquitination resulting in remodeling of the hippocampal neurons as well as increase in N-methyl-D-aspartate receptor 1 (NR1) subunit cell surface expression. Meanwhile, miR-181c might rescue the cellular activity from ischemia/hypoxia. These results indicated a novel miRNA-mediated mechanism involving miR-181c and TRIM2 in the cognitive impairment induced by CCH and provided a rationale for the development of miRNA-based strategies for prevention of dementia.

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“…Exposure to a higher dose of VPA in rodents results in reduced brain weight [250, 265], whereas a lower dose does not affect brain weight [331]. Acute exposure at a high dose reduces cortical thickness [250], whereas chronic exposure to a low dose increases cortical thickness [307].…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

“…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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Elevated microRNA-181c and microRNA-30d levels in the enlarged amygdala of the valproic acid rat model of autism

Cited by 44 publications

References 74 publications

Maternal immune activation alters brain microRNA expression in mouse offspring

Maternal immune activation alters brain microRNA expression in mouse offspring

MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Autism spectrum disorder: neuropathology and animal models

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