Cargando…
Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberran...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998961/ https://www.ncbi.nlm.nih.gov/pubmed/29901787 http://dx.doi.org/10.1093/cercor/bhy046 |
_version_ | 1783331334128664576 |
---|---|
author | Zerbi, Valerio Ielacqua, Giovanna D Markicevic, Marija Haberl, Matthias Georg Ellisman, Mark H A-Bhaskaran, Arjun Frick, Andreas Rudin, Markus Wenderoth, Nicole |
author_facet | Zerbi, Valerio Ielacqua, Giovanna D Markicevic, Marija Haberl, Matthias Georg Ellisman, Mark H A-Bhaskaran, Arjun Frick, Andreas Rudin, Markus Wenderoth, Nicole |
author_sort | Zerbi, Valerio |
collection | PubMed |
description | Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1(−/y)) and contactin-associated (CNTNAP2(−/−)) knockout mice. Young Fmr1(−/y) mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2(−/−) mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes. |
format | Online Article Text |
id | pubmed-5998961 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-59989612018-06-18 Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories Zerbi, Valerio Ielacqua, Giovanna D Markicevic, Marija Haberl, Matthias Georg Ellisman, Mark H A-Bhaskaran, Arjun Frick, Andreas Rudin, Markus Wenderoth, Nicole Cereb Cortex Original Articles Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1(−/y)) and contactin-associated (CNTNAP2(−/−)) knockout mice. Young Fmr1(−/y) mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2(−/−) mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes. Oxford University Press 2018-07 2018-04-18 /pmc/articles/PMC5998961/ /pubmed/29901787 http://dx.doi.org/10.1093/cercor/bhy046 Text en © The Author(s) 2018. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Articles Zerbi, Valerio Ielacqua, Giovanna D Markicevic, Marija Haberl, Matthias Georg Ellisman, Mark H A-Bhaskaran, Arjun Frick, Andreas Rudin, Markus Wenderoth, Nicole Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories |
title | Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories |
title_full | Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories |
title_fullStr | Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories |
title_full_unstemmed | Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories |
title_short | Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories |
title_sort | dysfunctional autism risk genes cause circuit-specific connectivity deficits with distinct developmental trajectories |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998961/ https://www.ncbi.nlm.nih.gov/pubmed/29901787 http://dx.doi.org/10.1093/cercor/bhy046 |
work_keys_str_mv | AT zerbivalerio dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT ielacquagiovannad dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT markicevicmarija dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT haberlmatthiasgeorg dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT ellismanmarkh dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT abhaskaranarjun dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT frickandreas dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT rudinmarkus dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories AT wenderothnicole dysfunctionalautismriskgenescausecircuitspecificconnectivitydeficitswithdistinctdevelopmentaltrajectories |