GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation

Siu-Pok Yee,Cody Tieu Forsyth,Dong-Yun Jiang,Gong Chen,Zheng Wu,Yi Hu

doi:10.1186/s13041-018-0375-6

Siu-Pok Yee, Cody Tieu Forsyth + Show 4 more

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https://doi.org/10.1186/s13041-018-0375-6

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Abstract

Schizophrenia (SCZ) is a severe mental disorder characterized by delusion, hallucination, and cognitive deficits. We have previously identified from schizophrenia patients a loss-of-function mutation Arg215→His215 (R215H) of neuroligin 2 (NLGN2) gene, which encodes a cell adhesion molecule critical for GABAergic synapse formation and function. Here, we generated a novel transgenic mouse line with neuroligin-2 (NL2) R215H mutation. The single point mutation caused a significant loss of NL2 protein in vivo, reduced GABAergic transmission, and impaired hippocampal activation. Importantly, R215H KI mice displayed anxiety-like behavior, impaired pre-pulse inhibition (PPI), cognition deficits and abnormal stress responses, recapitulating several key aspects of schizophrenia-like behaviors. Our results demonstrate a significant impact of a single point mutation NL2 R215H on brain functions, providing a novel animal model for the study of schizophrenia and neuropsychiatric disorders.

Highlights

Schizophrenia (SCZ) is a chronic neuropsychiatric disorder caused by both genetic and environmental factors
We demonstrate that the R215H knock-in (KI) mice show severe GABAergic deficits and display anxiety-like behavior seen in global NL2 Knock out (KO) mice [1, 3, 61], and impaired pre-pulse inhibition, cognitive deficits, and abnormal stress responses which are not reported in global NL2 KO mice
Generation of neuroligin-2 R215H mutant mice Following our original discovery of a loss-of-function mutation R215H of NL2 in SCZ patients [56], we generated the NL2 R215H mutant mice by introducing the same R215H mutation into the exon 4 of Nlgn2 gene in the mouse genome via homologous recombination (Fig. 1a)

Summary

Introduction

Schizophrenia (SCZ) is a chronic neuropsychiatric disorder caused by both genetic and environmental factors. It is featured by long-standing delusion and hallucination (psychosis), and cognitive deficits [17, 27, 39]. SCZ is a highly heritable disorder [55] with a complex genetic basis. Neuroligins (NLGNs) are a family of synaptic adhesion molecules highly expressed in the brain and are ligands for another group of cell adhesion molecules neurexins (NRXNs) [26]. There are five neuroligin genes (neuroligin-1, − 2, − 3, − 4, and − 5) in humans and four in mice (neuroligin 1–4). Neuroligin-1, − 2, and − 3 are close homologs between human and mice.

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