Non-invasive brain stimulation therapy for autism spectrum disorder (ASD) has shown beneficial effects. Recently, we and others demonstrated that visual sensory stimulation using rhythmic 40 Hz light flicker effectively improved cognitive deficits in mouse models of Alzheimer’s disease and stroke. However, whether rhythmic visual 40 Hz light flicker stimulation can ameliorate behavioral deficits in ASD remains unknown. Here, we show that 16p11.2 deletion female mice exhibit a strong social novelty deficit, which was ameliorated by treatment with a long-term 40 Hz light stimulation. The elevated power of local-field potential (LFP) in the prefrontal cortex (PFC) of 16p11.2 deletion female mice was also effectively reduced by 40 Hz light treatment. Importantly, the 40 Hz light flicker reversed the excessive excitatory neurotransmission of PFC pyramidal neurons without altering the firing rate and the number of resident PFC neurons. Mechanistically, 40 Hz light flicker evoked adenosine release in the PFC to modulate excessive excitatory neurotransmission of 16p11.2 deletion female mice. Elevated adenosine functioned through its cognate A₁ receptor (A₁R) to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the A₁R using a specific antagonist DPCPX or knocking down the A₁R in the PFC using a shRNA completely ablated the beneficial effects of 40 Hz light flicker. Thus, this study identified adenosine as a novel neurochemical mediator for ameliorating social novelty deficit by reducing excitatory neurotransmission during 40 Hz light flicker treatment. The 40 Hz light stimulation warrants further development as a non-invasive ASD therapeutics.

非侵入性脑刺激疗法对自闭症谱系障碍（ASD）已显示出有益的效果。最近，我们和其他人证明，使用有节奏的 40 Hz 光闪烁进行视觉感官刺激可以有效改善阿尔茨海默病和中风小鼠模型的认知缺陷。然而，有节奏的视觉 40 Hz 光闪烁刺激是否可以改善自闭症谱系障碍 (ASD) 的行为缺陷仍不清楚。在这里，我们发现 16p11.2 缺失的雌性小鼠表现出强烈的社交新颖性缺陷，这种缺陷可以通过长期 40 Hz 光刺激治疗得到改善。 40 Hz 光处理也有效降低了 16p11.2 缺失雌性小鼠前额皮质 (PFC) 局部场电位 (LFP) 功率的升高。重要的是，40 Hz 的光闪烁逆转了 PFC 锥体神经元的过度兴奋性神经传递，而没有改变放电率和驻留 PFC 神经元的数量。从机制上讲，40 Hz 光闪烁会引起 PFC 中的腺苷释放，从而调节 16p11.2 缺失雌性小鼠的过度兴奋性神经传递。升高的腺苷通过其同源 A ₁受体 (A ₁ R) 发挥作用，抑制过度兴奋性神经传递并缓解社会新鲜感缺陷。事实上，使用特定拮抗剂 DPCPX阻断 A ₁ R 或使用 shRNA 敲低 PFC 中的A ₁ R 完全消除了 40 Hz 光闪烁的有益效果。因此，这项研究将腺苷确定为一种新型神经化学介质，可通过减少 40 Hz 光闪烁治疗期间的兴奋性神经传递来改善社交新颖性缺陷。 40 Hz 光刺激值得进一步开发为非侵入性 ASD 疗法。