Huang Qiyun, Pereira Andreia C, Velthuis Hester, Wong Nichol M L, Ellis Claire L, Ponteduro Francesca M, Dimitrov Mihail, Kowalewski Lukasz, Lythgoe David J, Rotaru Diana, Edden Richard A E, Leonard Alison, Ivin Glynis, Ahmad Jumana, Pretzsch Charlotte M, Daly Eileen, Murphy Declan G M, McAlonan Gráinne M
Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
Sci Transl Med. 2022 Jan 5;14(626):eabg7859. doi: 10.1126/scitranslmed.abg7859.
Sensory atypicalities in autism spectrum disorder (ASD) are thought to arise at least partly from differences in γ-aminobutyric acid (GABA) receptor function. However, the evidence to date has been indirect, arising from correlational studies in patients and preclinical models. Here, we evaluated the role of GABA receptor directly, in 44 adults ( = 19 ASD). Baseline concentration of occipital lobe GABA+ (GABA plus coedited macromolecules) was measured using proton magnetic resonance spectroscopy (H-MRS). Steady-state visual evoked potential (SSVEP) elicited by a passive visual surround suppression paradigm was compared after double-blind randomized oral administration of placebo or 15 to 30 mg of arbaclofen (STX209), a GABA type B (GABA) receptor agonist. In the placebo condition, the neurotypical SSVEP response was affected by both the foreground stimuli contrast and background interference (suppression). In ASD, however, all stimuli conditions had equal salience and background suppression of the foreground response was weaker. In the placebo condition, although there was no difference in GABA+ between groups, GABA+ concentration positively correlated with response to maximum foreground contrast during maximum background interference in neurotypicals, but not ASD. In neurotypicals, sensitivity to visual stimuli was disrupted by 30 mg of arbaclofen, whereas in ASD, it was made more “typical” and visual processing differences were abolished. Hence, differences in GABAergic function are fundamental to autistic (visual) sensory neurobiology and are modulated by GABA activity.
自闭症谱系障碍（ASD）中的感觉异常被认为至少部分源于γ-氨基丁酸（GABA）受体功能的差异。然而，迄今为止的证据都是间接的，来自对患者和临床前模型的相关性研究。在此，我们直接评估了GABA受体的作用，研究对象为44名成年人（n = 19名ASD患者）。使用质子磁共振波谱（H-MRS）测量枕叶GABA+（GABA加上共编辑大分子）的基线浓度。在双盲随机口服安慰剂或15至30毫克阿巴氯芬（STX209，一种GABA B型（GABAB）受体激动剂）后，比较被动视觉环绕抑制范式诱发的稳态视觉诱发电位（SSVEP）。在安慰剂条件下，神经典型的SSVEP反应受到前景刺激对比度和背景干扰（抑制）的影响。然而，在ASD患者中，所有刺激条件的显著性相同，前景反应的背景抑制较弱。在安慰剂条件下，尽管两组之间的GABA+没有差异，但在神经典型个体中，GABA+浓度与最大背景干扰期间对最大前景对比度的反应呈正相关，而在ASD患者中则不然。在神经典型个体中，30毫克阿巴氯芬会破坏对视觉刺激的敏感性，而在ASD患者中，它会使反应更“典型”，视觉处理差异消失。因此，GABA能功能的差异是自闭症（视觉）感觉神经生物学的基础，并受GABA活性调节。
