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

Abstract

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.

The “don’t eat me” signal CD47 contributes to microglial phagocytosis defects and autism-like behaviors in 16p11.2 deletion mice

“…Consequently, 16p11.2 deletion mice exhibited a marked decrease in microglial phagocytic ability, increased synapse number, and excitatory transmission within the PFC. As a result, the 16p11.2 deletion mice display increased local field potential activity in the PFC, diminished long-range prefrontal connectivity (17), and thalamic-prefrontal miswiring and low-frequency neuronal synchronization reduction (21).…”

“…In fact, evidence suggests that the maturation and function of distinct neural circuits may potentially be linked to the molecular identity that microglia adopt across the brain (10,(14)(15)(16). Our recent studies using the 16p11.2 deletion mouse model demonstrated a significant reduction in microglia phagocytosis, enhanced excessive excitatory neurotransmission of the pyramidal neurons in the prefrontal cortex (PFC), and their linkage with social novelty deficit (17). However, the molecular mediators for microglial regulation of synaptic steady-state in the 16p11.2 deletion mouse brain remain unclear.…”

“…Individuals with 16p11.2 deletion exhibit impaired PFC connectivity with other brain regions involved in sociability functions (21). Immunohistochemical studies demonstrated elevated levels of dendritic spines in the 16p11.2 deletion mouse PFC, and electrophysiological data showed that 16p11.2 deletion mice have decreased PFC neuronal activity and abnormal NMDA receptor function (1,17,22). Chemogenetic activation of PFC could rescue synaptic and behavioral deficits in the mouse model of 16p11.2 deletion syndrome (22).…”