Brain Research Centre, Department of Neuroscience, School of Life Sciences, Southern University of Science and Technology, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, 518055, Guangdong, PR China.
The Brain Science Center, Beijing Institute of Basic Medical Sciences, 100850, Beijing, China.
Mol Psychiatry. 2024 Nov;29(11):3381-3394. doi: 10.1038/s41380-024-02596-4. Epub 2024 May 13.
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 A receptor (AR) to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the AR using a specific antagonist DPCPX or knocking down the AR 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在自闭症谱系障碍（ASD）方面显示出有益的效果。最近，我们和其他人证明，使用 40Hz 节律光闪烁的视觉感觉刺激可有效改善阿尔茨海默病和中风小鼠模型的认知缺陷。然而，节律性视觉 40Hz 光闪烁刺激是否能改善 ASD 的行为缺陷尚不清楚。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奇缺陷，而长期的 40Hz 光刺激治疗可改善这种缺陷。16p11.2 缺失的雌性小鼠前额叶皮层（PFC）局部场电位（LFP）的功率升高也可被 40Hz 光处理有效降低。重要的是，40Hz 光闪烁可逆转 PFC 锥体神经元过度兴奋的神经传递，而不改变神经元的放电率和驻留 PFC 神经元的数量。从机制上讲，40Hz 光闪烁可在前额叶皮层诱发腺苷释放，从而调节 16p11.2 缺失雌性小鼠过度兴奋的神经传递。升高的腺苷通过其同源 A 受体（AR）发挥作用，抑制过度兴奋的神经传递，缓解社交新奇缺陷。实际上，使用特定的拮抗剂 DPCPX 阻断 AR 或使用 shRNA 在前额叶皮层敲低 AR 均可完全消除 40Hz 光闪烁的有益作用。因此，这项研究确定了腺苷作为一种新型神经化学介质，通过减少 40Hz 光闪烁治疗期间的兴奋性神经传递来改善社交新奇缺陷。40Hz 光刺激作为一种非侵入性 ASD 治疗方法值得进一步开发。
