Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the basolateral amygdala–nucleus accumbens (BLA-NAc) glutamatergic circuit reduced SI and increased social avoidance in mice. Furthermore, we found that 2-arachidonoylglycerol (2-AG) endocannabinoid signaling reduced BLA-NAc glutamatergic activity and that pharmacological 2-AG augmentation via administration of JZL184, a monoacylglycerol lipase inhibitor, blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit markedly increased SI in the Shank3B^–/– mouse, an ASD model with substantial SI impairment, without affecting SI in WT mice. Finally, we demonstrated that JZL184 delivered systemically or directly to the NAc also normalized SI deficits in Shank3B^–/– mice, while ex vivo JZL184 application corrected aberrant NAc excitatory and inhibitory neurotransmission and reduced BLA-NAc–elicited feed-forward inhibition of NAc neurons in Shank3B^–/– mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASDs and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc.

中文翻译：

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内源性大麻素调节基底外侧杏仁核-伏隔核调节社交能力。

社会交往不足（SI）是自闭症谱系障碍（ASD）的核心症状。但是，显然缺乏社会赤字的治疗方法。阐明调节社交性的脑回路和神经调节信号系统可以促进对ASD病理生理学的更深入了解，并揭示针对ASD的新疗法。在这里，我们发现体内外侧基底杏仁核-伏隔核（BLA-NAc）谷氨酸能回路的光遗传激活减少了SI，并增加了小鼠的社交回避。此外，我们发现2-花生四烯酰甘油（2-AG）内源性大麻素信号传导降低了BLA-NAc谷氨酸能活性，并且通过施用单酰基甘油脂肪酶抑制剂JZL184增强了药理学2-AG，阻止了与体内BLA-NAc刺激相关的SI缺陷。另外，Shank3B ^{– / –}小鼠，一种ASD模型，具有严重的SI损伤，而不会影响WT小鼠的SI。最后，我们证明了JZL184全身或直接递送至NAc还可正常化Shank3B ^{– / –}小鼠的SI缺陷，而离体JZL184应用可纠正异常的NAc兴奋性和抑制性神经传递，并减少BLA-NAc引起的对NAc神经元的前馈抑制。在Shank3B ^{– / –}小鼠中。这些数据揭示了调节与ASD相关的社会功能的电路水平和神​​经调节机制，并表明2-AG增强可通过调节NAc中的兴奋性和抑制性神经传递来减少社会缺陷。