NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors

Hyejin Lee, Wangyong Shin, Kyungdeok Kim, Suho Lee, Eun Jae Lee, Jihye Kim, Hanseul Kweon, Eunee Lee, Haram Park, Muwon Kang, Esther Yang, Hyun Kim, Eunjoon Kim

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Abstract

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.

Original languageEnglish
Pages (from-to)e2005326
JournalPLoS biology
Volume17
Issue number6
DOIs
Publication statusPublished - 2019 Jun 1

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lee, H., Shin, W., Kim, K., Lee, S., Lee, E. J., Kim, J., Kweon, H., Lee, E., Park, H., Kang, M., Yang, E., Kim, H., & Kim, E. (2019). NGL-3 in the regulation of brain development, Akt/GSK3b signaling, long-term depression, and locomotive and cognitive behaviors. PLoS biology, 17(6), e2005326. https://doi.org/10.1371/journal.pbio.2005326