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NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors
Netrin-G ligand-3 (NGL-3) is a postsynaptic adhesion molecule known to directly interact with the excitatory postsynaptic scaffolding protein postsynaptic density-95 (PSD-95) and trans-synaptically with leukocyte common antigen-related (LAR) family receptor tyrosine phosphatases to regulate presynap...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550391/ https://www.ncbi.nlm.nih.gov/pubmed/31166939 http://dx.doi.org/10.1371/journal.pbio.2005326 |
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author | Lee, Hyejin Shin, Wangyong Kim, Kyungdeok Lee, Suho Lee, Eun-Jae Kim, Jihye Kweon, Hanseul Lee, Eunee Park, Haram Kang, Muwon Yang, Esther Kim, Hyun Kim, Eunjoon |
author_facet | Lee, Hyejin Shin, Wangyong Kim, Kyungdeok Lee, Suho Lee, Eun-Jae Kim, Jihye Kweon, Hanseul Lee, Eunee Park, Haram Kang, Muwon Yang, Esther Kim, Hyun Kim, Eunjoon |
author_sort | Lee, Hyejin |
collection | PubMed |
description | Netrin-G ligand-3 (NGL-3) is a postsynaptic adhesion molecule known to directly interact with the excitatory postsynaptic scaffolding protein postsynaptic density-95 (PSD-95) and trans-synaptically with leukocyte common antigen-related (LAR) family receptor tyrosine phosphatases to regulate presynaptic differentiation. Although NGL-3 has been implicated in the regulation of excitatory synapse development by in vitro studies, whether it regulates synapse development or function, or any other features of brain development and function, is not known. Here, we report that mice lacking NGL-3 (Ngl3(−/−) mice) show markedly suppressed normal brain development and postnatal survival and growth. A change of the genetic background of mice from pure to hybrid minimized these developmental effects but modestly suppressed N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated synaptic transmission in the hippocampus without affecting synapse development, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated basal transmission, and presynaptic release. Intriguingly, long-term depression (LTD) was near-completely abolished in Ngl3(−/−) mice, and the Akt/glycogen synthase kinase 3β (GSK3β) signaling pathway, known to suppress LTD, was abnormally enhanced. In addition, pharmacological inhibition of Akt, but not activation of NMDARs, normalized the suppressed LTD in Ngl3(−/−) mice, suggesting that Akt hyperactivity suppresses LTD. Ngl3(−/−) mice displayed several behavioral abnormalities, including hyperactivity, anxiolytic-like behavior, impaired spatial memory, and enhanced seizure susceptibility. Among them, the hyperactivity was rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-3 regulates brain development, Akt/GSK3β signaling, LTD, and locomotive and cognitive behaviors. |
format | Online Article Text |
id | pubmed-6550391 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-65503912019-06-17 NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors Lee, Hyejin Shin, Wangyong Kim, Kyungdeok Lee, Suho Lee, Eun-Jae Kim, Jihye Kweon, Hanseul Lee, Eunee Park, Haram Kang, Muwon Yang, Esther Kim, Hyun Kim, Eunjoon PLoS Biol Research Article Netrin-G ligand-3 (NGL-3) is a postsynaptic adhesion molecule known to directly interact with the excitatory postsynaptic scaffolding protein postsynaptic density-95 (PSD-95) and trans-synaptically with leukocyte common antigen-related (LAR) family receptor tyrosine phosphatases to regulate presynaptic differentiation. Although NGL-3 has been implicated in the regulation of excitatory synapse development by in vitro studies, whether it regulates synapse development or function, or any other features of brain development and function, is not known. Here, we report that mice lacking NGL-3 (Ngl3(−/−) mice) show markedly suppressed normal brain development and postnatal survival and growth. A change of the genetic background of mice from pure to hybrid minimized these developmental effects but modestly suppressed N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated synaptic transmission in the hippocampus without affecting synapse development, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated basal transmission, and presynaptic release. Intriguingly, long-term depression (LTD) was near-completely abolished in Ngl3(−/−) mice, and the Akt/glycogen synthase kinase 3β (GSK3β) signaling pathway, known to suppress LTD, was abnormally enhanced. In addition, pharmacological inhibition of Akt, but not activation of NMDARs, normalized the suppressed LTD in Ngl3(−/−) mice, suggesting that Akt hyperactivity suppresses LTD. Ngl3(−/−) mice displayed several behavioral abnormalities, including hyperactivity, anxiolytic-like behavior, impaired spatial memory, and enhanced seizure susceptibility. Among them, the hyperactivity was rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-3 regulates brain development, Akt/GSK3β signaling, LTD, and locomotive and cognitive behaviors. Public Library of Science 2019-06-05 /pmc/articles/PMC6550391/ /pubmed/31166939 http://dx.doi.org/10.1371/journal.pbio.2005326 Text en © 2019 Lee et al 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 author and source are credited. |
spellingShingle | Research Article Lee, Hyejin Shin, Wangyong Kim, Kyungdeok Lee, Suho Lee, Eun-Jae Kim, Jihye Kweon, Hanseul Lee, Eunee Park, Haram Kang, Muwon Yang, Esther Kim, Hyun Kim, Eunjoon NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors |
title | NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors |
title_full | NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors |
title_fullStr | NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors |
title_full_unstemmed | NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors |
title_short | NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors |
title_sort | ngl-3 in the regulation of brain development, akt/gsk3b signaling, long-term depression, and locomotive and cognitive behaviors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550391/ https://www.ncbi.nlm.nih.gov/pubmed/31166939 http://dx.doi.org/10.1371/journal.pbio.2005326 |
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