Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons

被引：67

作者：

Marro, Samuele G. ^{[1
,2
]}

Chanda, Soham ^{[1
,2
,5
,7
]}

Yang, Nan ^{[1
,2
,8
]}

Janas, Justyna A. ^{[1
,2
]}

Valperga, Giulio ^{[1
,2
]}

Trotter, Justin ^{[5
,6
]}

Zhou, Bo ^{[1
,2
,5
]}

Merril, Sean ^{[5
,6
]}

Yousif, Issa ^{[1
,2
]}

Shelby, Hannah ^{[1
,2
]}

Vogel, Hannes ^{[1
]}

Kalani, M. Yashar S. ^{[3
,4
]}

Sudhof, Thomas C. ^{[5
,6
]}

Wemig, Marius ^{[1
,2
]}

机构：

[1] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA

[3] Univ Virginia, Sch Med, Dept Neurosurg, Charlottesville, VA 22908 USA

[4] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA

[5] Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA

[6] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA

[7] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA

[8] Icahn Sch Med Mt Sinai, Black Family Stem Cell Inst, Friedman Brain Inst, Dept Neurosci, New York, NY 10029 USA

来源：

NEURON | 2019年 / 103卷 / 04期

关键词：

PLURIPOTENT STEM-CELLS; DE-NOVO MUTATIONS; VARIABLE PHENOTYPE; MOUSE MODEL; AUTISM; NLGN4; DELETION; GLIA; GENE; DIFFERENTIATION;

D O I：

10.1016/j.neuron.2019.05.043

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin- 4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.

引用

页码：617 / +

页数：16

共 59 条

[1] Neuroanatomy of autism [J].