Distinct Defects in Spine Formation or Pruning in Two Gene Duplication Mouse Models of Autism

Miao Wang,Wen-Jie Bian,Toru Takumi,Zilong Qiu,Xiu Xu,Xiang Yu,Huiping Li

doi:10.1007/s12264-017-0111-8

Abstract

Autism spectrum disorder (ASD) encompasses a complex set of developmental neurological disorders, characterized by deficits in social communication and excessive repetitive behaviors. In recent years, ASD is increasingly being considered as a disease of the synapse. One main type of genetic aberration leading to ASD is gene duplication, and several mouse models have been generated mimicking these mutations. Here, we studied the effects of MECP2 duplication and human chromosome 15q11-13 duplication on synaptic development and neural circuit wiring in the mouse sensory cortices. We showed that mice carrying MECP2 duplication had specific defects in spine pruning, while the 15q11-13 duplication mouse model had impaired spine formation. Our results demonstrate that spine pathology varies significantly between autism models and that distinct aspects of neural circuit development may be targeted in different ASD mutations. Our results further underscore the importance of gene dosage in normal development and function of the brain.

Highlights

Autism spectrum disorder (ASD) encompasses a wide range of neurological disorders with developmental origins, displaying a variety of symptoms and all including the key characteristics of impaired social interaction and excessive repetitive behaviors and/or restricted interests [1]
We showed that mice carrying Methyl-CpG-binding protein 2 (MECP2) duplication had specific defects in spine pruning, while the 15q11-13 duplication mouse model had impaired spine formation
Its lossof-function mutations result in Rett syndrome [32, 33, 39], while its overexpression leads to progressive neurological symptoms with ASD features

Summary

Introduction

Autism spectrum disorder (ASD) encompasses a wide range of neurological disorders with developmental origins, displaying a variety of symptoms and all including the key characteristics of impaired social interaction and excessive repetitive behaviors and/or restricted interests [1]. These behavioral abnormalities are thought to be caused by alterations in neural circuits. Based on accumulating evidence demonstrating defects in synaptic development and/or function in animal models of ASD and in patients, autism has been considered as the disease of synapse [2,3,4,5,6,7]. Spines undergo dramatic changes during development, in species ranging from rodents to humans [12,13,14,15,16,17,18,19]

Methods

Results

Conclusion