Inhibitory dysfunction in autism

 描述（由申请人提供）：自闭症谱系障碍（ASD）是一种复杂的大脑发育障碍，其特征是社交、沟通和重复行为困难，通常伴有感觉处理中断。最近一个潜在的统一神经生物学解释认为，ASD是由大脑内兴奋/抑制（E/I）平衡的破坏引起的。与E/I解释一致，最近在动物模型中的遗传和神经科学研究表明，在ASD中抑制性神经递质γ-氨基丁酸（GABA）信号传导可能被显著破坏。然而，GABA在ASD中的作用在很大程度上尚未在人类中进行测试。我们建议测试这一假设，即GABA皮质水平的变化引起神经回路的过度反应和反应不足，导致ASD的关键感觉和运动症状。重要的是，GABA信号非常适合药物治疗。因此，了解GABA信号如何在ASD中改变将开辟新的药理学治疗可能性。我们将使用最先进的磁共振波谱（MRS）技术来测量患有ASD的成年人和神经典型对照受试者的视觉、运动和听觉皮层中的GABA浓度。我们将使用功能磁共振成像测量诱发的感觉和运动反应，以表征这些区域的神经反应沿着感觉敏感性和运动相关症状的临床措施。最后，我们将使用fMRI来测量视觉系统中一个完善的抑制性神经回路的强度：环绕抑制。通过阐明抑制信号的功能，我们的结果将显着 进一步了解ASD的神经生物学原因。

 DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is a complex disorder of brain development characterized by difficulties in social interaction, communication, and repetitive behaviors and is often accompanied by disruptions of sensory processing. One recent and potentially unifying neurobiological explanation posits that ASD is caused by disruptions in the excitatory/inhibitory (E/I) balance within the brain. Consistent with the E/I explanation, recent genetic and neuroscience research in animal models suggest that inhibitory neurotransmitter gamma- aminobutyric acid (GABA) signaling may be significantly disrupted in ASD. However, the role of GABA in ASD remains largely untested in humans. We propose to test the hypothesis that changes in cortical levels of GABA give rise to over- and under- responsiveness of neural circuits leading to key sensory and motor symptoms of ASD. Critically, GABA signaling is highly amenable to pharmacological treatment. Thus, understanding how GABA signaling is altered in ASD will open up new pharmacological treatment possibilities. We will use state- of-the-art magnetic resonance spectroscopy (MRS) techniques to measure concentrations of GABA in adults with an ASD and neurotypical control subjects in visual, motor, and auditory cortices. We will use fMRI measures of evoked sensory and motor responses to characterize neural responsiveness in these regions along with clinical measures of sensory-sensitivity and motor-related symptoms. Finally, we will use fMRI to measure the strength of a well-established inhibitory neural circuit in the visual system: surround suppression. By elucidating the functioning of inhibitory signaling, our results will significantly advance understanding of the neurobiological causes of ASD.