Cargando…

Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients

Whereas aberrant brain connectivity is likely the core pathology of autism-spectrum disorder (ASD), studies do not agree as to whether hypo- or hyper-connectivity is the main underlying problem. Recent functional imaging studies have shown that, in most young ASD patients, cerebral cortical regions...

Descripción completa

Detalles Bibliográficos
Autores principales: Koh, Jae-Young, Lim, Joon Seo, Byun, Hyae-Ran, Yoo, Min-Heui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237964/
https://www.ncbi.nlm.nih.gov/pubmed/25182223
http://dx.doi.org/10.1186/s13041-014-0064-z
_version_ 1782345435970535424
author Koh, Jae-Young
Lim, Joon Seo
Byun, Hyae-Ran
Yoo, Min-Heui
author_facet Koh, Jae-Young
Lim, Joon Seo
Byun, Hyae-Ran
Yoo, Min-Heui
author_sort Koh, Jae-Young
collection PubMed
description Whereas aberrant brain connectivity is likely the core pathology of autism-spectrum disorder (ASD), studies do not agree as to whether hypo- or hyper-connectivity is the main underlying problem. Recent functional imaging studies have shown that, in most young ASD patients, cerebral cortical regions appear hyperconnected, and cortical thickness/brain size is increased. Collectively, these findings indicate that developing ASD brains may exist in an altered neurotrophic milieu. Consistently, some ASD patients, as well as some animal models of ASD, show increased levels of brain-derived neurotrophic factor (BDNF). However, how BDNF is upregulated in ASD is unknown. To address this question, we propose the novel hypothesis that a putative zinc-metalloprotease-BDNF (ZMB) axis in the forebrain plays a pivotal role in the development of hyperconnectivity and megalencephaly in ASD. We have previously demonstrated that extracellular zinc at micromolar concentrations can rapidly increase BDNF levels and phosphorylate the receptor tyrosine kinase TrkB via the activation of metalloproteases. The role of metalloproteases in ASD is still uncertain, but in fragile X syndrome, a monogenic disease with an autistic phenotype, the levels of MMP are increased. Early exposure to lipopolysaccharides (LPS) and other MMP activators such as organic mercurials also have been implicated in ASD pathogenesis. The resultant increases in BDNF levels at synapses, especially those involved in the zinc-containing, associative glutamatergic system may produce abnormal brain circuit development. Various genetic mutations that lead to ASD are also known to affect BDNF signaling: some down-regulate, and others up-regulate it. We hypothesize that, although both up- and down-regulation of BDNF may induce autism symptoms, only BDNF up-regulation is associated with the hyperconnectivity and large brain size observed in most young idiopathic ASD patients. To test this hypothesis, we propose to examine the ZMB axis in animal models of ASD. Synaptic zinc can be examined by fluorescence zinc staining. MMP activation can be measured by in situ zymography and Western blot analysis. Finally, regional levels of BDNF can be measured. Validating this hypothesis may shed light on the central pathogenic mechanism of ASD and aid in the identification of useful biomarkers and the development of preventive/therapeutic strategies.
format Online
Article
Text
id pubmed-4237964
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-42379642014-11-21 Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients Koh, Jae-Young Lim, Joon Seo Byun, Hyae-Ran Yoo, Min-Heui Mol Brain Review Whereas aberrant brain connectivity is likely the core pathology of autism-spectrum disorder (ASD), studies do not agree as to whether hypo- or hyper-connectivity is the main underlying problem. Recent functional imaging studies have shown that, in most young ASD patients, cerebral cortical regions appear hyperconnected, and cortical thickness/brain size is increased. Collectively, these findings indicate that developing ASD brains may exist in an altered neurotrophic milieu. Consistently, some ASD patients, as well as some animal models of ASD, show increased levels of brain-derived neurotrophic factor (BDNF). However, how BDNF is upregulated in ASD is unknown. To address this question, we propose the novel hypothesis that a putative zinc-metalloprotease-BDNF (ZMB) axis in the forebrain plays a pivotal role in the development of hyperconnectivity and megalencephaly in ASD. We have previously demonstrated that extracellular zinc at micromolar concentrations can rapidly increase BDNF levels and phosphorylate the receptor tyrosine kinase TrkB via the activation of metalloproteases. The role of metalloproteases in ASD is still uncertain, but in fragile X syndrome, a monogenic disease with an autistic phenotype, the levels of MMP are increased. Early exposure to lipopolysaccharides (LPS) and other MMP activators such as organic mercurials also have been implicated in ASD pathogenesis. The resultant increases in BDNF levels at synapses, especially those involved in the zinc-containing, associative glutamatergic system may produce abnormal brain circuit development. Various genetic mutations that lead to ASD are also known to affect BDNF signaling: some down-regulate, and others up-regulate it. We hypothesize that, although both up- and down-regulation of BDNF may induce autism symptoms, only BDNF up-regulation is associated with the hyperconnectivity and large brain size observed in most young idiopathic ASD patients. To test this hypothesis, we propose to examine the ZMB axis in animal models of ASD. Synaptic zinc can be examined by fluorescence zinc staining. MMP activation can be measured by in situ zymography and Western blot analysis. Finally, regional levels of BDNF can be measured. Validating this hypothesis may shed light on the central pathogenic mechanism of ASD and aid in the identification of useful biomarkers and the development of preventive/therapeutic strategies. BioMed Central 2014-09-03 /pmc/articles/PMC4237964/ /pubmed/25182223 http://dx.doi.org/10.1186/s13041-014-0064-z Text en Copyright © 2014 Koh et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Koh, Jae-Young
Lim, Joon Seo
Byun, Hyae-Ran
Yoo, Min-Heui
Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
title Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
title_full Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
title_fullStr Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
title_full_unstemmed Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
title_short Abnormalities in the zinc-metalloprotease-BDNF axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
title_sort abnormalities in the zinc-metalloprotease-bdnf axis may contribute to megalencephaly and cortical hyperconnectivity in young autism spectrum disorder patients
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237964/
https://www.ncbi.nlm.nih.gov/pubmed/25182223
http://dx.doi.org/10.1186/s13041-014-0064-z
work_keys_str_mv AT kohjaeyoung abnormalitiesinthezincmetalloproteasebdnfaxismaycontributetomegalencephalyandcorticalhyperconnectivityinyoungautismspectrumdisorderpatients
AT limjoonseo abnormalitiesinthezincmetalloproteasebdnfaxismaycontributetomegalencephalyandcorticalhyperconnectivityinyoungautismspectrumdisorderpatients
AT byunhyaeran abnormalitiesinthezincmetalloproteasebdnfaxismaycontributetomegalencephalyandcorticalhyperconnectivityinyoungautismspectrumdisorderpatients
AT yoominheui abnormalitiesinthezincmetalloproteasebdnfaxismaycontributetomegalencephalyandcorticalhyperconnectivityinyoungautismspectrumdisorderpatients