Nat Neurosci . . . Feng's team found the central nervous mechanism of sensory abnormalities in autism.

Autism spectrum disorder (ASD) is a group of syndromes composed of a variety of neurodevelopmental diseases. It has two core symptoms: social communication disorder, repetitive stereotyped behavior and narrow interest. It seriously limits the ability of patients to integrate into society, and brings a great burden to patients themselves, their families and even the whole society.the latest research shows that 90% of ASD patients have different degrees of sensory abnormalities: they feel too strong or too weak to the external normal sensory stimulation [1], which brings great difficulties to patients' daily life, and aggravates the core symptoms of ASD [2].the diagnostic and Statistical Manual of mental disorders (dsm-5), published by the American Psychiatric Association in May 2013, takes sensory abnormalities as one of the new diagnostic criteria for ASD, indicating the universality and importance of sensory abnormalities in the diagnosis of ASD.however, the mechanism of ASD dysesthesia is still unclear.on March 2, 2020, Professor Feng Guoping of MIT and Professor Christopher I. Moore of Brown University jointly published on the journal Nature Neuroscience the dysfunction of cortical GABAergic nerves leads to sensory hyper reactivity in a Shank3 model of In the long article of ASD, it was found that Shank3 gene knockout mice in ASD animal model had similar hypersensitivity phenotype with clinic. Further studies confirmed that the decrease of activity of such neurons caused by Shank3 gene deletion in the cerebral sensory cortex is the core mechanism of sensory hypersensitivity in this ASD animal model.this study revealed the key regulatory role of inhibitory interneurons in the occurrence of sensory abnormalities in ASD, and provided an important theoretical basis for the search for possible treatment strategies for ASD sensory abnormalities.the shell gene family (shank1-3) encodes postsynaptic dense body skeleton protein, which plays an important role in promoting excitatory synaptic formation, dendritic spine development and maintaining glutamate receptor function by interacting with PSD-95, sapap, homer1, glutamate ion receptor, metabolic receptor and other signal molecules and cytoskeleton proteins [3].clinical gene sequencing data show that single gene mutation of ship can lead to the occurrence of ASD [4].Shank3 knockout mice have become one of the important model animals for the study of ASD.in the past, the behavioral studies of Shank3 knockout mice were mostly focused on the aspects of social disorder and repetitive stereotyped actions, but few studies on the sensory and behavioral abnormalities of the ASD mice.firstly, the author used the moustache go / no go behavior test to find that Shank3 gene knockout mice had the phenotype of hypersensitivity to whisker stimulation, which was very similar to the clinical symptoms of tactile hypersensitivity in ASD patients (Fig. 1).Fig. 1: the sensitivity of Shank3 knockout mice to whisker stimulation increased. Then, using two-photon calcium imaging in vivo, we observed that the activity of excitatory neurons in the sensory cortex of conscious Shank3 knockout mice increased.however, previous studies in vitro showed that the number of synapses of excitatory neurons decreased and the synaptic transmission function of neurons decreased after Shank3 gene knockout [5]. These results are difficult to explain the phenomenon of tactile hypersensitivity and increased activity of excitatory neurons in sensory cortex observed in Shank3 knockout mice as a whole.the neurons in the sensory cortex are mainly composed of excitatory neurons and inhibitory interneurons.the afferent and efferent of information depend on excitatory neurons.these neurons account for 80% of the total number of cortical neurons, and their normal function is the guarantee for individuals to feel the information of external stimuli.the inhibitory interneurons, which account for 20% of the total number, regulate the afferent and efferent of excitatory neurons by controlling 80% of the excitatory neurons. the balance between excitatory neurons and inhibitory interneurons is the basis for maintaining normal brain function [6]. although the number of inhibitory interneurons is far less than that of excitatory neurons, the generation of normal sensation depends on the precise regulation of supra / subthreshold electrical activities of subcellular areas such as dendrites, axons and somas of excitatory neurons. this also means that the same damage of inhibitory interneurons may affect more excitatory neurons, resulting in a broader excitation inhibition imbalance. using two-photon calcium imaging in vivo, the authors did find that the activity of inhibitory interneurons in the sensory cortex of conscious Shank3 knockout mice was decreased. in order to further confirm the key role of decreased inhibitory interneurons activity caused by Shank3 gene deletion in the sensory hypersensitivity of this ASD mouse model, the authors used the inhibitory interneuron specific promoter to knock out Shank3 gene in the local intermediate neurons of the sensory cortex [7], and found that the activity of excitatory neurons in the sensory cortex of mice was significantly increased (Fig. 2), which was similar to that of Shank3 base The increase of excitatory neurons in the sensory cortex was observed in the whole knockout mice. in Fig. 2, the activity of excitatory neurons in the sensory cortex increased after Shank3 gene knockout. Only in the inhibitory interneurons in the sensory cortex, could specific knockout of Shank3 gene also cause tactile hypersensitivity in animals? This is confirmed by the results of go / no go beard behavior experiment (Fig. 3). in addition, the authors also reduced the activity of local interneurons in the sensory cortex through chemical genetics technology, which can also simulate the tactile hypersensitivity of mice. Fig. 3: the specific knockout of Shank3 gene in the intermediate neurons of sensory cortex can lead to tactile hypersensitivity in mice, and sensory abnormalities are common in autistic patients, which brings great difficulties to patients' daily life. this study reveals the important role of inhibitory interneurons in the sensory impairment of autism, provides an important reference for us to understand the neurobiological mechanism of autism sensory abnormalities, and provides a theoretical basis for looking for possible treatment strategies for autism sensory abnormalities. Dr. Chen Qian and Dr. Christopher A. Deister are co first authors of the paper. Professor Feng Guoping and Professor Christopher I. Moore are the co authors of the paper. the work has also been strongly supported by Professor Lu Zhonghua, Institute of brain cognition and brain disease, Shenzhen Institute of advanced technology, Chinese Academy of Sciences, and Professor Liao Weiping and Professor Shi Yiwu from the Institute of neuroscience, the Second Affiliated Hospital of Guangzhou Medical University. Amso, D., Haas, S., Tenenbaum, e., markant, J. & amp; shenkopf, S. J. bottom-up attention orientation in young children with audit. Journal of audit and development disorders 44, 664-673, doi:10.1007/s10803-013-1925-5 (2014).2. Robertson,C. E. & Baron-Cohen, S. Sensory perception in autism. Nature reviews. Neuroscience 18,671-684, doi:10.1038/nrn.2017.112 (2017).3.Sheng,M. & Kim, E. The Shank family of scaffold proteins. Journal of cell science 113( Pt 11), 1851-1856 (2000).4.Leblond, C. S. et al. Meta-analysis of SHANKMutations in Autism Spectrum Disorders: a gradient of severity in cognitiveimpairments. PLoS genetics 10, e1004580, doi:10.1371/journal.pgen.1004580 (2014).5. Peca,J. et al. Shank3 mutant mice displayautistic-like behaviours and striatal dysfunction. Nature 472, 437-442, doi:10.1038/nature09965 (2011).6. Nelson, S. B. & Valakh, V. Excitatory/Inhibitory Balance and Circuit Homeostasis inAutism Spectrum Disorders. Neuron 87, 684-698, doi:10.1016/j.neuron.2015.07.033 (2015)7.Dimidschstein,J. et al. A viral strategy fortargeting and manipulating interneurons across vertebrate species. Nature neuroscience 19, 1743-1749, doi:10.1038/nn.4430 (2016). NAT cell biol | breakthrough bottleneck! The team of he aibin / Cheng Heping / Xiao Wenlei realized the panoramic real-time record of mouse heart development on March 3, 2020: the first clinical trial of AAV gene therapy for X-linked retinitis pigmentosa showed great potential. The new progress of therapeutic hepatitis B vaccine on March 3, 2020 was revealed by Zhu Mingzhao group. The new immune mechanism of nano vaccine targeting lymph node was revealed by Zhu Mingzhao group