title: Elevated microRNA-181c and microRNA-30d levels in the enlarged amygdala of the valproic acid rat model of autism.
abstract: Autism spectrum disorders are severe neurodevelopmental disorders, marked by impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. Accumulating evidence suggests that dysfunction of the amygdala may be partially responsible for the impairment of social behavior that is a hallmark feature of ASD. Our studies suggest that a valproic acid (VPA) rat model of ASD exhibits an enlargement of the amygdala as compared to controls rats, similar to that observed in adolescent ASD individuals. Since recent research suggests that altered neuronal development and morphology, as seen in ASD, may result from a common post-transcriptional process that is under tight regulation by microRNAs (miRs), we examined genome-wide transcriptomics expression in the amygdala of rats prenatally exposed to VPA, and detected elevated miR-181c and miR-30d expression levels as well as dysregulated expression of their cognate mRNA targets encoding proteins involved in neuronal system development. Furthermore, selective suppression of miR-181c function attenuates neurite outgrowth and branching, and results in reduced synaptic density in primary amygdalar neurons in vitro. Collectively, these results implicate the small non-coding miR-181c in neuronal morphology, and provide a framework of understanding how dysregulation of a neurodevelopmentally relevant miR in the amygdala may contribute to the pathophysiology of ASD.
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: N F M
authors.initials: NF
authors.lastname: Olde Loohuis
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Kole
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Glennon
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Karel
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Van der Borg
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Van Gemert
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Van den Bosch
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Meinhardt
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Kos
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Shahabipour
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Tiesinga
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: G J M
authors.initials: GJ
authors.lastname: Martens
authors.affiliation: Laboratory of Molecular Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Kaplan
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: J R
authors.initials: JR
authors.lastname: Homberg
authors.affiliation: Department of Neuroinformatics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands. Electronic address: a.aschrafi@donders.ru.nl.
authors.forename: A
authors.initials: A
authors.lastname: Aschrafi
mesh_terms: D000679:Amygdala / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001321:Autistic Disorder / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012919:Social Behavior; D059467:Transcriptome; D014635:Valproic Acid
chemical_list: C581717:MIRN181 microRNA, rat; C556157:MIRN30 microRNA, rat; D035683:MicroRNAs; D014635:Valproic Acid
keywords: Amygdala; Autism spectrum disorder; Gene networks; MicroRNA; Neurodevelopmental disorder; Rat model of autism; Valproic acid