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Research Article

Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate

Fumitoshi Irie, Hedieh Badie-Mahdavi, and Yu Yamaguchi
  1. Genetic Disease Program, Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037

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PNAS first published March 12, 2012; https://doi.org/10.1073/pnas.1117881109
Fumitoshi Irie
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Hedieh Badie-Mahdavi
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Yu Yamaguchi
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  • For correspondence: yyamaguchi@sanfordburnham.org
  1. Edited by Thomas C. Südhof, Stanford University School of Medicine, Palo Alto, CA, and approved February 13, 2012 (received for review October 31, 2011)

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Abstract

Heparan sulfate regulates diverse cell-surface signaling events, and its roles in the development of the nervous system recently have been increasingly uncovered by studies using genetic models carrying mutations of genes encoding enzymes for its synthesis. On the other hand, the role of heparan sulfate in the physiological function of the adult brain has been poorly characterized, despite several pieces of evidence suggesting its role in the regulation of synaptic function. To address this issue, we eliminated heparan sulfate from postnatal neurons by conditionally inactivating Ext1, the gene encoding an enzyme essential for heparan sulfate synthesis. Resultant conditional mutant mice show no detectable morphological defects in the cytoarchitecture of the brain. Remarkably, these mutant mice recapitulate almost the full range of autistic symptoms, including impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features. Mapping of neuronal activation by c-Fos immunohistochemistry demonstrates that neuronal activation in response to social stimulation is attenuated in the amygdala in these mice. Electrophysiology in amygdala pyramidal neurons shows an attenuation of excitatory synaptic transmission, presumably because of the reduction in the level of synaptically localized AMPA-type glutamate receptors. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism.

  • glycosaminoglycan
  • conditional knockout
  • multiple hereditary exostoses

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: yyamaguchi{at}sanfordburnham.org.
  • Author contributions: F.I. and Y.Y. designed research; F.I. and H.B.-M. performed research; F.I. and Y.Y. analyzed data; and Y.Y. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1117881109/-/DCSupplemental.

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Autistic deficits in heparan sulfate mutant mice
Fumitoshi Irie, Hedieh Badie-Mahdavi, Yu Yamaguchi
Proceedings of the National Academy of Sciences Mar 2012, 201117881; DOI: 10.1073/pnas.1117881109

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Autistic deficits in heparan sulfate mutant mice
Fumitoshi Irie, Hedieh Badie-Mahdavi, Yu Yamaguchi
Proceedings of the National Academy of Sciences Mar 2012, 201117881; DOI: 10.1073/pnas.1117881109
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