Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD 21201, USA.
Neuroscience. 2021 Dec 15;479:180-191. doi: 10.1016/j.neuroscience.2021.09.013. Epub 2021 Sep 24.
Autism Spectrum Disorder (ASD) is a multifaceted condition associated with difficulties in social interaction and communication. It also shares several comorbidities with other neurodevelopmental conditions. Intensive research examining the molecular basis and characteristics of ASD has revealed an association with a large number and variety of low-penetrance genes. Many of the variants associated with ASD are in genes underlying pathways involved in long-term potentiation (LTP) or depression (LTD). These mechanisms then control the tuning of neuronal connections in response to experience by modifying and trafficking ionotropic glutamate receptors at the post-synaptic areas. Despite the high genetic heterogeneity in ASD, surface trafficking of the α-amino-3-hydroxy-5-Methyl-4-isoxazolepropionate (AMPA) receptor is a vulnerable pathway in ASD. In this review, we discuss autism-related alterations in the trafficking of AMPA receptors, whose surface density and composition at the post-synapse determine the strength of the excitatory connection between neurons. We highlight genes associated with neurodevelopmental conditions that share the autism comorbidity, including Fragile X syndrome, Rett Syndrome, and Tuberous Sclerosis, as well as the autism-risk genes NLGNs, IQSEC2, DOCK4, and STXBP5, all of which are involved in regulating AMPAR trafficking to the post-synaptic surface.
自闭症谱系障碍（ASD）是一种多方面的疾病，与社交互动和沟通困难有关。它还与其他神经发育障碍共享几种共病。对 ASD 的分子基础和特征进行的深入研究揭示了与大量低外显率基因的关联。与 ASD 相关的许多变体存在于参与长时程增强（LTP）或抑郁（LTD）的途径的基因中。这些机制通过在突触后区域修饰和运输离子型谷氨酸受体来控制神经元连接对经验的调整。尽管 ASD 存在高度的遗传异质性，但 AMPA 受体的表面转运是 ASD 的一个脆弱途径。在这篇综述中，我们讨论了与自闭症相关的 AMPA 受体转运的改变，突触后部位的 AMPA 受体表面密度和组成决定了神经元之间兴奋性连接的强度。我们强调了与自闭症共病的神经发育障碍相关的基因，包括脆性 X 综合征、雷特综合征和结节性硬化症，以及自闭症风险基因 NLGNs、IQSEC2、DOCK4 和 STXBP5，它们都参与调节 AMPAR 向突触后表面的转运。
