Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, CA, 92697-4625, United States.
Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, CA, 92697-4625, United States.
Neuropharmacology. 2017 Nov;126:38-47. doi: 10.1016/j.neuropharm.2017.08.029. Epub 2017 Aug 24.
Autism spectrum disorder (ASD) is associated with two core symptoms (social communication deficits and stereotyped repetitive behaviors) in addition to a number of comorbidities. There are no FDA-approved drugs for the core symptoms and the changes that underlie these behaviors are not fully understood. One hypothesis is an imbalance of the excitation (E)/inhibition (I) ratio with excessive E and diminished I occurring in specific neuronal circuits. Data suggests that both gamma-aminobutyric acid (GABA) and α7 nicotinic acetylcholine receptors (nAChRs) significantly impact E/I. BTBR Ttf/J (BTBR) mice are a model that display an autism-like phenotype with impaired social interaction and stereotyped behavior. A β2/3-subunit containing GABA receptor (GABAR) subtype selective positive allosteric modulator (PAM), 2-261, and an α7 nAChR subtype selective PAM, AVL-3288, were tested in social approach and repetitive self-grooming paradigms. 2-261 was active in the social approach but not the self-grooming paradigm, whereas AVL-3288 was active in both. Neither compound impaired locomotor activity. Modulating α7 nAChRs alone may be sufficient to correct these behavioral and cognitive deficits. GABAergic and nicotinic compounds are already in various stages of clinical testing for treatment of the core symptoms and comorbidities associated with ASD. Our findings and those of others suggest that compounds that have selective activities at GABAR subtypes and the α7 nAChR may address not only the core symptoms, but many of the associated comorbidities as well and warrant further investigation in other models of ASD.
自闭症谱系障碍（ASD）除了存在多种合并症外，还与两个核心症状（社交沟通障碍和刻板重复行为）有关。目前还没有获得美国食品和药物管理局（FDA）批准的用于治疗核心症状的药物，而且这些行为背后的变化也尚未完全了解。有一种假说认为，兴奋性（E）/抑制性（I）比率失衡，特定神经元回路中出现过度 E 和减弱 I。数据表明，γ-氨基丁酸（GABA）和α7 烟碱型乙酰胆碱受体（nAChRs）都对 E/I 有显著影响。BTBR Ttf/J（BTBR）小鼠是一种具有自闭症样表型的模型，表现为社交互动受损和刻板行为。一种含有β2/3 亚基的 GABA 受体（GABAR）亚型选择性正变构调节剂（PAM）2-261 和一种α7 nAChR 亚型选择性 PAM AVL-3288，在社交接近和重复自我梳理范式中进行了测试。2-261 在社交接近中有效，但在自我梳理中无效，而 AVL-3288 在两种范式中均有效。这两种化合物均不影响运动活动。单独调节α7 nAChR 可能足以纠正这些行为和认知缺陷。GABA 能和烟碱化合物已经处于治疗 ASD 核心症状和合并症的不同临床测试阶段。我们的发现和其他人的发现表明，对 GABAR 亚型和α7 nAChR 具有选择性活性的化合物不仅可以治疗核心症状，还可以治疗许多相关的合并症，值得在其他 ASD 模型中进一步研究。
