NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation

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Netrin-G ligand 2 (NGL-2)/LRRC4, implicated in autism spectrum disorders and schizophrenia, is a leucine-rich repeat-containing postsynaptic adhesion molecule that interacts intracellularly with the excitatory postsynaptic scaffolding protein PSD-95 and trans-synaptically with the presynaptic adhesion molecule netrin-G2. Functionally, NGL-2 regulates excitatory synapse development and synaptic transmission. However, whether it regulates synaptic plasticity and disease-related specific behaviors is not known. Here, we report that mice lacking NGL-2 (Lrrc4(-/-) mice) show suppressed N-MethylD-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampus. NGL-2 associates with NMDARs through both PSD-95-dependent and -independent mechanisms. Moreover, Lrrc4(-/-) mice display mild social interaction deficits and repetitive behaviors that are rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-2 promotes synaptic stabilization of NMDARs, regulates NMDAR-dependent synaptic plasticity, and prevents autistic-like behaviors from developing in mice, supporting the hypothesis that NMDAR dysfunction contributes to autism spectrum disorders.
Publisher
CELL PRESS
Issue Date
2018-06
Language
English
Article Type
Article
Citation

CELL REPORTS, v.23, no.13, pp.3839 - 3851

ISSN
2211-1247
DOI
10.1016/j.celrep.2018.05.087
URI
http://hdl.handle.net/10203/244900
Appears in Collection
BS-Journal Papers(저널논문)
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