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An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum

Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been...

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Autores principales: Lai, Esther Suk King, Nakayama, Hisako, Miyazaki, Taisuke, Nakazawa, Takanobu, Tabuchi, Katsuhiko, Hashimoto, Kouichi, Watanabe, Masahiko, Kano, Masanobu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273702/
https://www.ncbi.nlm.nih.gov/pubmed/34262438
http://dx.doi.org/10.3389/fncir.2021.676891
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author Lai, Esther Suk King
Nakayama, Hisako
Miyazaki, Taisuke
Nakazawa, Takanobu
Tabuchi, Katsuhiko
Hashimoto, Kouichi
Watanabe, Masahiko
Kano, Masanobu
author_facet Lai, Esther Suk King
Nakayama, Hisako
Miyazaki, Taisuke
Nakazawa, Takanobu
Tabuchi, Katsuhiko
Hashimoto, Kouichi
Watanabe, Masahiko
Kano, Masanobu
author_sort Lai, Esther Suk King
collection PubMed
description Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10–15 (P10–15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.
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spelling pubmed-82737022021-07-13 An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum Lai, Esther Suk King Nakayama, Hisako Miyazaki, Taisuke Nakazawa, Takanobu Tabuchi, Katsuhiko Hashimoto, Kouichi Watanabe, Masahiko Kano, Masanobu Front Neural Circuits Neuroscience Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10–15 (P10–15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD. Frontiers Media S.A. 2021-06-28 /pmc/articles/PMC8273702/ /pubmed/34262438 http://dx.doi.org/10.3389/fncir.2021.676891 Text en Copyright © 2021 Lai, Nakayama, Miyazaki, Nakazawa, Tabuchi, Hashimoto, Watanabe and Kano. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Lai, Esther Suk King
Nakayama, Hisako
Miyazaki, Taisuke
Nakazawa, Takanobu
Tabuchi, Katsuhiko
Hashimoto, Kouichi
Watanabe, Masahiko
Kano, Masanobu
An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum
title An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum
title_full An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum
title_fullStr An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum
title_full_unstemmed An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum
title_short An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum
title_sort autism-associated neuroligin-3 mutation affects developmental synapse elimination in the cerebellum
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273702/
https://www.ncbi.nlm.nih.gov/pubmed/34262438
http://dx.doi.org/10.3389/fncir.2021.676891
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