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Brainstem motor neuron dysmorphology and excitatory/inhibitory imbalance in an animal model of autism
Affiliations- Department of Anatomy, Lake Erie College of Osteopathic Medicine, Erie, PA, United States
open access
Abstract
Background: Autism spectrum disorder (ASD) is a developmental disorder associated with in utero exposure to the antiepileptic valproic acid (VPA) in humans, and similar exposure serves as a validated animal model. Animals exposed to VPA in utero have a number of structural, function and behavioural deficits associated with ASD. Furthermore, VPA-exposed animals have shorter body lengths, lower body and brain weights. This difference in body weight may result from impaired caloric intake due to impaired oropharyngeal function.
Materials and methods: Specifically, it is hypothesized that in utero VPA exposure results in fewer lower motor neurons associated with feeding behaviours, that surviving neurons will exhibit dysmorphology and altered balance of excitatory and inhibitory inputs. Further, it is hypothesized that VPA exposure will result in altered oropharyngeal musculature that will impact skull morphology.
Results: These hypotheses were investigated using quantitative morphometrics and immunofluorescence.
Conclusions: Results support dysmorphology and excitatory/inhibitory imbalance and these alterations may contribute to dysphagia and poor weight gain in VPA-exposed animals
Abstract
Background: Autism spectrum disorder (ASD) is a developmental disorder associated with in utero exposure to the antiepileptic valproic acid (VPA) in humans, and similar exposure serves as a validated animal model. Animals exposed to VPA in utero have a number of structural, function and behavioural deficits associated with ASD. Furthermore, VPA-exposed animals have shorter body lengths, lower body and brain weights. This difference in body weight may result from impaired caloric intake due to impaired oropharyngeal function.
Materials and methods: Specifically, it is hypothesized that in utero VPA exposure results in fewer lower motor neurons associated with feeding behaviours, that surviving neurons will exhibit dysmorphology and altered balance of excitatory and inhibitory inputs. Further, it is hypothesized that VPA exposure will result in altered oropharyngeal musculature that will impact skull morphology.
Results: These hypotheses were investigated using quantitative morphometrics and immunofluorescence.
Conclusions: Results support dysmorphology and excitatory/inhibitory imbalance and these alterations may contribute to dysphagia and poor weight gain in VPA-exposed animals
Keywords
trigeminal, vagus, swallowing
About this articleTitle
Brainstem motor neuron dysmorphology and excitatory/inhibitory imbalance in an animal model of autism
Journal
Issue
Article type
Original article
Pages
863-873
Published online
2021-09-28
Page views
4148
Article views/downloads
688
DOI
Pubmed
Bibliographic record
Folia Morphol 2022;81(4):863-873.
Keywords
trigeminal
vagus
swallowing
Authors
H. Alhelo
R. J. Kulesza
References (42)- Allen DA. Autistic spectrum disorders: clinical presentation in preschool children. J Child Neurol. 1988; 3 Suppl: S48–S56.
- Anomal RF, de Villers-Sidani E, Brandão JA, et al. Impaired processing in the primary auditory cortex of an animal model of autism. Front Syst Neurosci. 2015; 9: 158.
- APA.org. [Internet]. What Is Autism Spectrum Disorder? c2018. https://www.psychiatry.org/patients-families/autism/what-is-autism-spectrum-disorder.
- Baio J, Wiggins L, Christensen DL, et al. Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, united states, 2014. MMWR Surveill Summ. 2018; 67(6): 1–23.
- Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005; 23(2-3): 183–187.
- Baxter AJ, Brugha TS, Erskine HE, et al. The epidemiology and global burden of autism spectrum disorders. Psychol Med. 2015; 45(3): 601–613.
- Binkerd PE, Rowland JM, Nau H, et al. Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats. Fundam Appl Toxicol. 1988; 11(3): 485–493.
- Burdan F, Rozylo-Kalinowska I, Katarzyna Rozylo T, et al. A new rapid radiological procedure for routine teratological use in bone ossification assessment: a supplement for staining methods. Teratology. 2002; 66(6): 315–325.
- CDC.gov. [Internet]. (2018, 2018-04-26). Data and Statistics | Autism Spectrum Disorder (ASD) | NCBDDD | CDC; c2018. https://www.cdc.gov/ncbddd/autism/data.html.
- Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013; 309(16): 1696–1703.
- Driesch Avd. A guide to the measurement of animal bones from archaeological sites : as developed by the Institut für Palaeoanatomie, Domestikationsforschung und Geschichte der Tiermedizin of the University of Munich. Cambridge, Mass., Peabody Museum of Archaeology and Ethnology, Harvard University; 1976.
- Dubiel A, Kulesza RJ. Prenatal valproic acid exposure disrupts tonotopic c-Fos expression in the rat brainstem. Neuroscience. 2015; 311: 349–361.
- Engineer CT, Centanni TM, Im KW, et al. Speech sound discrimination training improves auditory cortex responses in a rat model of autism. Front Syst Neurosci. 2014; 8: 137.
- Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009; 65(6): 591–598.
- Foran L, Kupelian C, Laroia S, et al. Neonatal exposure to monosodium glutamate results in dysmorphology of orofacial lower motor neurons. Folia Morphol. 2017; 76(4): 582–589.
- Fujimura K, Mitsuhashi T, Shibata S, et al. In utero exposure to valproic acid induces neocortical dysgenesis via dysregulation of neural progenitor cell proliferation/differentiation. J Neurosci. 2016; 36(42): 10908–10919.
- Gandal MJ, Edgar JC, Ehrlichman RS, et al. Validating γ oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry. 2010; 68(12): 1100–1106.
- Harris AJ. Critical periods in the development of motoneurons. Rev Neurol (Paris). 1988; 144(11): 643–647.
- Holstege G, Graveland G, Bijker-Biemond C, et al. Location of motoneurons innervating soft palate, pharynx and upper esophagus. Anatomical evidence for a possible swallowing center in the pontine reticular formation. An HRP and autoradiographical tracing study. Brain Behav Evol. 1983; 23(1-2): 47–62.
- Iijima Y, Behr K, Iijima T, et al. Distinct defects in synaptic differentiation of neocortical neurons in response to prenatal valproate exposure. Sci Rep. 2016; 6: 27400.
- Kim KiC, Kim P, Go HS, et al. Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder. J Neurochem. 2013; 124(6): 832–843.
- Lukose R, Schmidt E, Wolski TP, et al. Malformation of the superior olivary complex in an animal model of autism. Brain Res. 2011; 1398: 102–112.
- Main SL, Kulesza RJ. Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia. Neuroscience. 2017; 340: 34–47.
- Mansour Y, Ahmed S, Kulesza R. Abnormal morphology and subcortical projections to the medial geniculate in an animal of autism. Exp Brain Res. 2021; 239(2): 381–400.
- Mansour Y, Mangold S, Chosky D, et al. Auditory midbrain hypoplasia and dysmorphology after prenatal valproic acid exposure. Neuroscience. 2019; 396: 79–93.
- Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000; 37(7): 489–497.
- Mychasiuk R, Richards S, Nakahashi A, et al. Effects of rat prenatal exposure to valproic acid on behaviour and neuro-anatomy. Dev Neurosci. 2012; 34(2-3): 268–276.
- Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol. 2009; 28(1): 1–10.
- Pang YW, Ge SN, Nakamura KC, et al. Axon terminals expressing vesicular glutamate transporter VGLUT1 or VGLUT2 within the trigeminal motor nucleus of the rat: origins and distribution patterns. J Comp Neurol. 2009; 512(5): 595–612.
- Rodier PM, Ingram JL, Tisdale B, et al. Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol. 1996; 370(2): 247–261, doi: 10.1002/(SICI)1096-9861(19960624)370:2<247::AID-CNE8>3.0.CO;2-2.
- Rueden CT, Schindelin J, Hiner MC, et al. ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinformatics. 2017; 18(1): 529.
- Schneider T, Roman A, Basta-Kaim A, et al. Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology. 2008; 33(6): 728–740.
- Sheard P, McCaig CD, Harris AJ. Critical periods in rat motoneuron development. Dev Biol. 1984; 102(1): 21–31.
- Travers JB, Yoo JE, Chandran R, et al. Neurotransmitter phenotypes of intermediate zone reticular formation projections to the motor trigeminal and hypoglossal nuclei in the rat. J Comp Neurol. 2005; 488(1): 28–47.
- Twachtman-Reilly J, Amaral SC, Zebrowski PP. Addressing feeding disorders in children on the autism spectrum in school-based settings: physiological and behavioral issues. Lang Speech Hear Serv Sch. 2008; 39(2): 261–272.
- Vorhees CV. Teratogenicity and developmental toxicity of valproic acid in rats. Teratology. 1987; 35(2): 195–202.
- Werling DM, Geschwind DH. Sex differences in autism spectrum disorders. Curr Opin Neurol. 2013; 26(2): 146–153.
- WHO.int. [Internet]. Autism spectrum disorders; c2018. https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders (cited 22 May 2019).
- Williams G, King J, Cunningham M, et al. Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol. 2001; 43(3): 202–206.
- Zhang J, Luo P, Pendlebury WW. Light and electron microscopic observations of a direct projection from mesencephalic trigeminal nucleus neurons to hypoglossal motoneurons in the rat. Brain Res. 2001; 917(1): 67–80.
- Zimmerman R, Patel R, Smith A, et al. Repeated prenatal exposure to valproic acid results in auditory brainstem hypoplasia and reduced calcium binding protein immunolabeling. Neuroscience. 2018; 377: 53–68.
- Zimmerman R, Smith A, Fech T, et al. In utero exposure to valproic acid disrupts ascending projections to the central nucleus of the inferior colliculus from the auditory brainstem. Exp Brain Res. 2020; 238(3): 551–563.
