Aberrant brain functional and structural developments in MECP2 duplication rats.

Abstract

Transgenic animal models with homologous etiology provide a promising way to pursue the neurobiological substrates of the behavioral deficits in autism spectrum disorder (ASD). Gain-of-function mutations of MECP2 cause MECP2 duplication syndrome, a severe neurological disorder with core symptoms of ASD. However, abnormal brain developments underlying the autistic-like behavioral deficits of MECP2 duplication syndrome are rarely investigated. To this end, a human MECP2 duplication (MECP2-DP) rat model was created by the bacterial artificial chromosome transgenic method. Functional and structural magnetic resonance imaging (MRI) with high-field were performed on 16 male MECP2-DP rats and 15 male wildtype rats at postnatal 28 days, 42 days, and 56 days old. Multimodal fusion analyses guided by locomotor-relevant metrics and social novelty time separately were applied to identify abnormal brain networks associated with diverse behavioral deficits induced by MECP2 duplication. Aberrant functional developments of a core network primarily composed of the dorsal medial prefrontal cortex (dmPFC) and retrosplenial cortex (RSP) were detected to associate with diverse behavioral phenotypes in MECP2-DP rats. Altered developments of gray matter volume were detected in the hippocampus and thalamus. We conclude that gain-of-function mutations of MECP2 induce aberrant functional activities in the default-mode-like network and aberrant volumetric changes in the brain, resulting in autistic-like behavioral deficits. Our results gain critical insights into the biomarker of MECP2 duplication syndrome and the neurobiological underpinnings of the behavioral deficits in ASD.

• Authors: Ming Xu, Shile Qi, Vince Calhoun, Jiankun Dai, Bin Yu, Kaiwei Zhang, Mengchao Pei, Chenjian Li, Yusheng Wei, Rongtao Jiang, Dongmei Zhi, Zhimin Huang, Zilong Qiu, Zhifeng Liang, Jing Sui
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 173 Pg. 105838 (10 15 2022) ISSN: 1095-953X [Electronic] United States
• PMID: 35985556 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Mecp2 protein, rat
• Methyl-CpG-Binding Protein 2

Topics

• Animals
• Autism Spectrum Disorder (diagnostic imaging, genetics)
• Brain (metabolism)
• Brain Mapping (methods)
• Humans
• Male
• Mental Retardation, X-Linked (genetics)
• Methyl-CpG-Binding Protein 2 (genetics, metabolism)
• Rats