PDF(Pubmed)
Abstract：
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social communication and social interaction, restricted and repetitive behavior, and interests. The core symptoms of ASD are associated with deficits in mesocorticolimbic dopamine pathways that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). AST-001 is an investigational product currently in a phase 3 clinical trial for treating the core symptoms of ASD, with L-serine as the API (active pharmaceutical ingredient). Because the causes of ASD are extremely heterogeneous, a single genetic ASD model cannot represent all autism models. In this paper, we used the VPA-exposed model, which is more general and widely used than a single genetic model, but this is also one of the animal models of autism. Herein, we conducted experiments to demonstrate the efficacy of AST-001 as L-Serine that alters the regulation of the firing rate in dopamine neurons by inhibiting small conductance Ca2+-activated K+ channels (SK channels). Through these actions, AST-001 improved sociability and social novelty by rescuing the intrinsic excitabilities of dopamine neurons in VPA-exposed ASD mouse models that showed ASD-related behavioral abnormalities. It is thought that this effect of improving social deficits in VPA-exposed ASD mouse models is due to AST-001 normalizing aberrant SK channel activities that slowed VTA dopamine neuron firing. Overall, these findings suggest that AST-001 may be a potential therapeutic agent for ASD patients, and that its mechanism of action may involve the regulation of dopamine neuron activity and the improvement of social interaction.
摘要：
自闭症谱系障碍（ASD）是一种复杂的神经发育障碍，其特征是社会交往和社会交往受损。限制和重复的行为，和利益。ASD的核心症状与从腹侧被盖区（VTA）投射到伏隔核（NAc）和内侧前额叶皮层（mPFC）的中皮层边缘多巴胺途径的缺陷有关。AST-001是目前正在进行3期临床试验的研究产品，用于治疗ASD的核心症状，以L-丝氨酸作为API(活性药物成分)。因为ASD的病因非常不同，单个遗传ASD模型不能代表所有自闭症模型。在本文中,我们使用了VPA暴露模型，比单个遗传模型更普遍和广泛使用，但这也是自闭症的动物模型之一。在这里，我们进行了实验，以证明AST-001作为L-丝氨酸的功效，通过抑制小电导Ca2激活的K通道（SK通道）来改变多巴胺神经元放电率的调节。通过这些行动,AST-001通过挽救暴露于VPA的ASD小鼠模型中多巴胺神经元的内在兴奋性来改善社交能力和社会新颖性，该模型显示出与ASD相关的行为异常。据认为，在暴露于VPA的ASD小鼠模型中改善社会缺陷的这种作用是由于AST-001使异常的SK通道活动正常化，从而减慢了VTA多巴胺神经元的放电。总的来说,这些结果表明，AST-001可能是ASD患者的潜在治疗剂，其作用机制可能涉及多巴胺神经元活性的调节和社会交往的改善。
