Adenosine mediates the amelioration of social novelty deficits during rhythmic light treatment of 16p11.2+/- female mice

Abstract

Abstract Non-invasive brain stimulation therapy for autism spectrum disorder (ASD) has shown beneficial effects. Recently, 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+/− 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+/− 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+/− female mice. Elevated adenosine functioned through its cognate A1 receptor to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the A1 receptor using a specific antagonist DPCPX or knockdown the A1 receptor in the PFC using an shRNA completely ablated the beneficial effects of 40 Hz light flicker. Thus, this study identified adenosine as a novel neurochemical cause for ameliorating social novelty deficit through the reduction of excitatory neurotransmission by the 40 Hz light flicker. The 40 Hz light stimulation warrants further development as a non-invasive ASD therapeutics.