Cargando…
MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders
Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in t...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094851/ https://www.ncbi.nlm.nih.gov/pubmed/27779093 http://dx.doi.org/10.7554/eLife.20059 |
_version_ | 1782465182999511040 |
---|---|
author | Harrington, Adam J Raissi, Aram Rajkovich, Kacey Berto, Stefano Kumar, Jaswinder Molinaro, Gemma Raduazzo, Jonathan Guo, Yuhong Loerwald, Kris Konopka, Genevieve Huber, Kimberly M Cowan, Christopher W |
author_facet | Harrington, Adam J Raissi, Aram Rajkovich, Kacey Berto, Stefano Kumar, Jaswinder Molinaro, Gemma Raduazzo, Jonathan Guo, Yuhong Loerwald, Kris Konopka, Genevieve Huber, Kimberly M Cowan, Christopher W |
author_sort | Harrington, Adam J |
collection | PubMed |
description | Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice. DOI: http://dx.doi.org/10.7554/eLife.20059.001 |
format | Online Article Text |
id | pubmed-5094851 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-50948512016-11-04 MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders Harrington, Adam J Raissi, Aram Rajkovich, Kacey Berto, Stefano Kumar, Jaswinder Molinaro, Gemma Raduazzo, Jonathan Guo, Yuhong Loerwald, Kris Konopka, Genevieve Huber, Kimberly M Cowan, Christopher W eLife Neuroscience Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice. DOI: http://dx.doi.org/10.7554/eLife.20059.001 eLife Sciences Publications, Ltd 2016-10-25 /pmc/articles/PMC5094851/ /pubmed/27779093 http://dx.doi.org/10.7554/eLife.20059 Text en © 2016, Harrington et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience Harrington, Adam J Raissi, Aram Rajkovich, Kacey Berto, Stefano Kumar, Jaswinder Molinaro, Gemma Raduazzo, Jonathan Guo, Yuhong Loerwald, Kris Konopka, Genevieve Huber, Kimberly M Cowan, Christopher W MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders |
title | MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders |
title_full | MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders |
title_fullStr | MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders |
title_full_unstemmed | MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders |
title_short | MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders |
title_sort | mef2c regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094851/ https://www.ncbi.nlm.nih.gov/pubmed/27779093 http://dx.doi.org/10.7554/eLife.20059 |
work_keys_str_mv | AT harringtonadamj mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT raissiaram mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT rajkovichkacey mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT bertostefano mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT kumarjaswinder mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT molinarogemma mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT raduazzojonathan mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT guoyuhong mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT loerwaldkris mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT konopkagenevieve mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT huberkimberlym mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders AT cowanchristopherw mef2cregulatescorticalinhibitoryandexcitatorysynapsesandbehaviorsrelevanttoneurodevelopmentaldisorders |