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MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission

The MIR137 locus is a replicated genetic risk factor for schizophrenia. The risk-associated allele is reported to increase miR-137 expression and miR-137 overexpression alters synaptic transmission in mouse hippocampus. We investigated the cellular mechanisms underlying these observed effects in mou...

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Autores principales: He, Enqi, Lozano, Miguel A Gonzalez, Stringer, Sven, Watanabe, Kyoko, Sakamoto, Kensuke, den Oudsten, Frank, Koopmans, Frank, Giamberardino, Stephanie N, Hammerschlag, Anke, Cornelisse, L Niels, Li, Ka Wan, van Weering, Jan, Posthuma, Danielle, Smit, August B, Sullivan, Patrick F, Verhage, Matthijs
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961183/
https://www.ncbi.nlm.nih.gov/pubmed/29635364
http://dx.doi.org/10.1093/hmg/ddy089
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author He, Enqi
Lozano, Miguel A Gonzalez
Stringer, Sven
Watanabe, Kyoko
Sakamoto, Kensuke
den Oudsten, Frank
Koopmans, Frank
Giamberardino, Stephanie N
Hammerschlag, Anke
Cornelisse, L Niels
Li, Ka Wan
van Weering, Jan
Posthuma, Danielle
Smit, August B
Sullivan, Patrick F
Verhage, Matthijs
author_facet He, Enqi
Lozano, Miguel A Gonzalez
Stringer, Sven
Watanabe, Kyoko
Sakamoto, Kensuke
den Oudsten, Frank
Koopmans, Frank
Giamberardino, Stephanie N
Hammerschlag, Anke
Cornelisse, L Niels
Li, Ka Wan
van Weering, Jan
Posthuma, Danielle
Smit, August B
Sullivan, Patrick F
Verhage, Matthijs
author_sort He, Enqi
collection PubMed
description The MIR137 locus is a replicated genetic risk factor for schizophrenia. The risk-associated allele is reported to increase miR-137 expression and miR-137 overexpression alters synaptic transmission in mouse hippocampus. We investigated the cellular mechanisms underlying these observed effects in mouse hippocampal neurons in culture. First, we correlated the risk allele to expression of the genes in the MIR137 locus in human postmortem brain. Some evidence for increased MIR137HG expression was observed, especially in hippocampus of the disease-associated genotype. Second, in mouse hippocampal neurons, we confirmed previously observed changes in synaptic transmission upon miR-137 overexpression. Evoked synaptic transmission and spontaneous release were 50% reduced. We identified defects in release probability as the underlying cause. In contrast to previous observations, no evidence was obtained for selective synaptic vesicle docking defects. Instead, ultrastructural morphometry revealed multiple effects of miR-137 overexpression on docking, active zone length and total vesicle number. Moreover, proteomic analyses of neuronal protein showed that expression of Syt1 and Cplx1, previously reported as downregulated upon miR-137 overexpression, was unaltered. Immunocytochemistry of synapses overexpressing miR-137 showed normal Synaptotagmin1 and Complexin1 protein levels. Instead, our proteomic analyses revealed altered expression of genes involved in synaptogenesis. Concomitantly, synaptogenesis assays revealed 31% reduction in synapse formation. Taken together, these data show that miR-137 regulates synaptic function by regulating synaptogenesis, synaptic ultrastructure and synapse function. These effects are plausible contributors to the increased schizophrenia risk associated with miR-137 overexpression.
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spelling pubmed-59611832018-06-06 MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission He, Enqi Lozano, Miguel A Gonzalez Stringer, Sven Watanabe, Kyoko Sakamoto, Kensuke den Oudsten, Frank Koopmans, Frank Giamberardino, Stephanie N Hammerschlag, Anke Cornelisse, L Niels Li, Ka Wan van Weering, Jan Posthuma, Danielle Smit, August B Sullivan, Patrick F Verhage, Matthijs Hum Mol Genet Articles The MIR137 locus is a replicated genetic risk factor for schizophrenia. The risk-associated allele is reported to increase miR-137 expression and miR-137 overexpression alters synaptic transmission in mouse hippocampus. We investigated the cellular mechanisms underlying these observed effects in mouse hippocampal neurons in culture. First, we correlated the risk allele to expression of the genes in the MIR137 locus in human postmortem brain. Some evidence for increased MIR137HG expression was observed, especially in hippocampus of the disease-associated genotype. Second, in mouse hippocampal neurons, we confirmed previously observed changes in synaptic transmission upon miR-137 overexpression. Evoked synaptic transmission and spontaneous release were 50% reduced. We identified defects in release probability as the underlying cause. In contrast to previous observations, no evidence was obtained for selective synaptic vesicle docking defects. Instead, ultrastructural morphometry revealed multiple effects of miR-137 overexpression on docking, active zone length and total vesicle number. Moreover, proteomic analyses of neuronal protein showed that expression of Syt1 and Cplx1, previously reported as downregulated upon miR-137 overexpression, was unaltered. Immunocytochemistry of synapses overexpressing miR-137 showed normal Synaptotagmin1 and Complexin1 protein levels. Instead, our proteomic analyses revealed altered expression of genes involved in synaptogenesis. Concomitantly, synaptogenesis assays revealed 31% reduction in synapse formation. Taken together, these data show that miR-137 regulates synaptic function by regulating synaptogenesis, synaptic ultrastructure and synapse function. These effects are plausible contributors to the increased schizophrenia risk associated with miR-137 overexpression. Oxford University Press 2018-06-01 2018-04-04 /pmc/articles/PMC5961183/ /pubmed/29635364 http://dx.doi.org/10.1093/hmg/ddy089 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 Articles
He, Enqi
Lozano, Miguel A Gonzalez
Stringer, Sven
Watanabe, Kyoko
Sakamoto, Kensuke
den Oudsten, Frank
Koopmans, Frank
Giamberardino, Stephanie N
Hammerschlag, Anke
Cornelisse, L Niels
Li, Ka Wan
van Weering, Jan
Posthuma, Danielle
Smit, August B
Sullivan, Patrick F
Verhage, Matthijs
MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission
title MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission
title_full MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission
title_fullStr MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission
title_full_unstemmed MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission
title_short MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission
title_sort mir137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961183/
https://www.ncbi.nlm.nih.gov/pubmed/29635364
http://dx.doi.org/10.1093/hmg/ddy089
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