Department of Neurosciences, Faculty of Medicine, University of Montreal, Montréal QC H3T 1C5, Canada.
CHU Ste-Justine Research Center, Montréal, QC H3T 1C5, Canada.
Proc Natl Acad Sci U S A. 2023 Jan 10;120(2):e2208963120. doi: 10.1073/pnas.2208963120. Epub 2023 Jan 3.
Layer 5 (L5) pyramidal neurons receive predictive and sensory inputs in a compartmentalized manner at their apical and basal dendrites, respectively. To uncover how integration of sensory inputs is affected in autism spectrum disorders (ASD), we used two-photon glutamate uncaging to activate spines in the basal dendrites of L5 pyramidal neurons from a mouse model of Fragile X syndrome (FXS), the most common genetic cause of ASD. While subthreshold excitatory inputs integrate linearly in wild-type animals, surprisingly those with FXS summate sublinearly, contradicting what would be expected of sensory hypersensitivity classically associated with ASD. We next investigated the mechanism underlying this sublinearity by performing knockdown of the regulatory β4 subunit of BK channels, which rescued the synaptic integration, a result that was corroborated with numerical simulations. Taken together, these findings suggest that there is a differential impairment in the integration of feedforward sensory and feedback predictive inputs in L5 pyramidal neurons in FXS and potentially other forms of ASD, as a result of specifically localized subcellular channelopathies. These results challenge the traditional view that FXS and other ASD are characterized by sensory hypersensitivity, proposing instead a hyposensitivity of sensory inputs and hypersensitivity of predictive inputs onto cortical neurons.
第 5 层（L5）锥体神经元分别在其顶树突和基底树突以分隔的方式接收预测性和感觉性输入。为了揭示感觉性输入的整合在自闭症谱系障碍（ASD）中是如何受到影响的，我们使用双光子谷氨酸光解的方法来激活脆性 X 综合征（FXS）小鼠模型中 L5 锥体神经元基底树突的棘突，FXS 是 ASD 最常见的遗传原因。虽然在野生型动物中，亚阈兴奋性输入呈线性整合，但令人惊讶的是，FXS 动物的输入呈亚线性总和，这与经典上与 ASD 相关的感觉过敏不符。接下来，我们通过进行 BK 通道的调节β4 亚基的敲低来研究这种亚线性的机制，这挽救了突触整合，这一结果得到了数值模拟的证实。总之，这些发现表明，在 FXS 和其他形式的 ASD 中，L5 锥体神经元中前馈感觉和反馈预测输入的整合存在差异损伤，这是由于特定的细胞内通道病的结果。这些结果挑战了 FXS 和其他 ASD 的特征是感觉过敏的传统观点，而是提出了感觉输入的低敏性和皮质神经元的预测输入的超敏性。
