Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD
Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD
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DOI：
10.1038/s41593-020-0598-6
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发表时间：
2020-03-02
影响因子：
25
通讯作者：
Feng, Guoping
中科院分区：
文献类型：
--
作者：
Chen, Qian;Deister, Christopher A.;Feng, Guoping
对感觉输入的过度反应性是自闭症谱系障碍患者（ASD）的常见且令人衰弱的症状，但是尚未完全了解神经基础的感觉异常。在这里，我们检查了ASD的shank3b（ - / - ）小鼠模型的新皮层中感觉知觉的神经表示。在Vibrissa运动检测任务中，雄性和雌性Shank3b（ - / - ）小鼠对触觉刺激更敏感。体内种群钙成像在颤音原发性体感皮层（VS1）中显示，在金字塔神经元中自发性和刺激引起的诱发发射增加，但中间神经元的活性降低。 VS1抑制性中间神经元中Shank3的优先删除导致锥体神经元多动症，并提高了Vibrissa运动检测任务中的刺激灵敏度。这些发现提供了证据表明，皮质GABA能中神经元的功能障碍在ASD的Shank3小鼠模型中在感觉高反应性中起关键作用，并确定了探索治疗干预措施的潜在细胞靶标。表明Shank3b-Knockout小鼠对触觉感觉刺激表现出超敏反应，并且体感皮质中的中间神经元功能障碍有助于这种自闭症小鼠模型中的感觉超反应。
Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B(-/-) mouse model of ASD. Male and female Shank3B(-/-) mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.Chen, Deister et al. show that Shank3B-knockout mice display hypersensitivity to tactile sensory stimulation and that dysfunction of interneurons in somatosensory cortex contributes to the sensory hyper-reactivity in this mouse model of autism.