TY - JOUR
T1 - NGL-3 in the regulation of brain development, akt/gsk3b signaling, long-term depression, and locomotive and cognitive behaviors
AU - Lee, Hyejin
AU - Shin, Wangyong
AU - Kim, Kyungdeok
AU - Lee, Suho
AU - Lee, Eun Jae
AU - Kim, Jihye
AU - Kweon, Hanseul
AU - Lee, Eunee
AU - Park, Haram
AU - Kang, Muwon
AU - Yang, Esther
AU - Kim, Hyun
AU - Kim, Eunjoon
N1 - Funding Information:
Institute for Basic Science (grant number IBS-R002-D1). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Research Foundation of Korea (grant number NRF-2017M3C7A1079692). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Lee et al.
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067477026&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.2005326
DO - 10.1371/journal.pbio.2005326
M3 - Article
C2 - 31166939
AN - SCOPUS:85067477026
VL - 17
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 6
M1 - e2005326
ER -