Department of Neurology.
Neuroscience Interdepartmental Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095.
J Neurosci. 2019 Jan 16;39(3):412-419. doi: 10.1523/JNEUROSCI.1734-18.2018. Epub 2018 Dec 6.
Autism spectrum disorders are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in autism spectrum disorders could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic two-photon microscopy to image dendritic spines and axon "en passant" boutons of layer 2/3 pyramidal neurons in S1 of male and female WT and KO mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhance sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in KO mice. In contrast, axon "en passant" boutons dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of KO mice to modulate postsynaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS. Very few longitudinal imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience.
自闭症谱系障碍通常与非典型感觉处理和感觉过敏有关，这可能导致适应不良的行为，如触觉防御。自闭症谱系障碍中这种改变的感觉感知可能是由于早期大脑发育过程中与经验相关的回路成熟过程中断引起的。在这里，我们测试了这样一个假设，即在脆性 X 综合征 (FXS) 中，初级体感皮层 (S1) 神经元的突触结构在发育过程中不受新感觉信息的调节，FXS 是自闭症的常见遗传原因。我们使用慢性双光子显微镜来成像 S1 中第 2/3 层锥体神经元的树突棘和轴突“en passant”末梢，WT 和 KO 小鼠，FXS 的模型。我们发现，在出生后第二周短暂（过夜）暴露于明显增强的感觉输入会导致 WT 小鼠的棘密度显著增加，但 KO 小鼠则不然。相比之下，在两种基因型的小鼠中，轴突“en passant”末梢的动力学对这种新感觉体验均无动于衷。我们推测，KO 小鼠无法响应增加的感觉输入来调节突触后动力学，而在 S1 皮层中首次出现感觉信息处理时，这可能在 FXS 中的感觉处理改变中起作用。很少有纵向成像研究调查了早期新生小鼠的突触结构和动力学。此外，这些研究往往侧重于感觉输入剥夺的影响，而在正常大脑发育过程中很少发生这种过程。早期新生成像实验至关重要，因为包括自闭症在内的多种神经发育障碍可能是由于在发育关键期传入感觉输入塑造回路的方式发生改变所致。在这项研究中，我们专注于脆性 X 综合征的小鼠模型，并展示了树突棘如何对短暂的新感觉体验不敏感。
