Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome.

Chaojuan Yang; Yonglu Tian; Feng SU; Yangzhen Wang; Mengna Liu; Hongyi Wang; Yaxuan Cui; Peijiang Yuan; Xiangning LI; Anan LI; Hui Gong; Qingming Luo; Desheng Zhu; Peng Cao; Yunbo Liu; Xunli Wang; Min-hua Luo; Fuqiang XU; Wei Xiong; Liecheng Wang; Xiang-yao LI; Chen Zhang

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Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome.

Author: Chaojuan YANG ¹ ; Yonglu TIAN ¹ ; Feng SU ² ; Yangzhen WANG ² ; Mengna LIU ¹ ; Hongyi WANG ² ; Yaxuan CUI ¹ ; Peijiang YUAN ³ ; Xiangning LI ⁴ ; Anan LI ⁴ ; Hui GONG ⁴ ; Qingming LUO ⁴ ; Desheng ZHU ¹ ; Peng CAO ⁵ ; Yunbo LIU ⁶ ; Xunli WANG ⁷ ; Min-Hua LUO ⁸ ; Fuqiang XU ⁹ ; Wei XIONG ¹⁰ ; Liecheng WANG ¹¹ ; Xiang-Yao LI ¹² ; Chen ZHANG ¹³
Author Information

1. State Key Laboratory of Membrane Biology, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences, Peking University, Beijing, 100871, China.
2. School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China.
3. School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, China.
4. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, 430074, China.
5. State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences (CAS), Beijing, 100101, China.
6. Institute of Laboratory Animal Science, Peking Union Medical College/Chinese Academy of Medical Science, Beijing, 100021, China.
7. Laboratory Animal Center, Fujian University of Tradition Chinese Medicine, Fuzhou, 350122, China.
8. State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and, Intelligence Technology, Wuhan Institute of Virology, CAS, Wuhan, 430071, China.
9. Center for Brain Science, Key Laboratory of Magnetic Resonance in Biological Systems and State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, CAS, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Wuhan, 430071, China.
10. School of Life Sciences, Tsinghua University, Beijing, 100084, China.
11. Department of Physiology, Anhui Medical University, Hefei, 230032, China.
12. Department of Physiology, Institute of Neuroscience and Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
13. State Key Laboratory of Membrane Biology, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences, Peking University, Beijing, 100871, China. czhang@ccmu.edu.cn.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: autism spectrum disorder; calcium imaging; fragile X syndrome; primary visual cortex; visual hypersensitivity
MeSH: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein/metabolism*; Fragile X Syndrome/metabolism*; Humans; Mice; Mice, Knockout; Neurons/metabolism*
From: Protein & Cell 2022;13(3):203-219
CountryChina
Language:English
Abstract: Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1^KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1^KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABA_A receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1^KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.