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

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

doi:10.1371/journal.pbio.2005326

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.

Highlights

Synaptic adhesion molecules regulate diverse aspects of synapse development, function, and plasticity
Metabotropic glutamate receptor-dependent long-term depression (LTD) was not affected at Ngl3−/−(Hyb) SC-Cornu Ammonis 1 (CA1) synapses (S4C Fig). These results collectively suggest that Ngl3 KO leads to moderate suppression of NMDA receptor (NMDAR)-dependent synaptic transmission and long-term potentiation (LTP) but near-complete suppression of LTD in the hippocampus
We found a strong increase in the phosphorylation levels of the serine/threonine kinase Akt at both Ser-308 and Ser-473 (Fig 4D), known to lie in the downstream of phosphatidyl inositol 3 kinase/3-phosphoinositide-dependent protein kinase 1 (PI3K/3-phosphoinositidedependent protein kinase 1 (PDK1)) and mammalian target of rapamycin complex 2, respectively [34]

Summary

Introduction

Synaptic adhesion molecules regulate diverse aspects of synapse development, function, and plasticity. In addition to NGL-3, LAR-RPTPs have recently been shown to interact with several other postsynaptic adhesion molecules, including TrkC, interleukin 1 receptor accessory protein like 1 (IL1RAPL1), interleukin 1 receptor accessory protein (IL1RAcP), Slit- and Trk-like proteins (Slitrk1–5), synaptic adhesion-like molecule 3 (SALM3), and SALM5 [19, 21,22,23,24,25,26,27,28,29,30] These trans-synaptic adhesion complexes constitute a rapidly expanding group of synaptic organizers, little is known about their differential functions. We found that Ngl3/Lrrc4b knockout (KO) in a pure C57BL/6J genetic background (termed Ngl3−/−(B6) mice) decreases birth rate, postnatal growth and survival, and brain development, whereas Ngl KO in a hybrid genetic background (Ngl3−/−(Hyb) mice) does not induce these neurodevelopmental features Instead, these latter mice display modestly reduced NMDAR- but not AMPAR-dependent synaptic transmission. These results implicate NGL-3 in the regulation of brain development and excitability, Akt/GSK3β signaling, LTD, and behaviors in vivo

Results

Discussion

Ethics statement