An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability

J Clin Invest. 2020 Apr 1;130(4):1728-1742. doi: 10.1172/JCI131752.


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.

Keywords: Neuroscience; Psychiatric diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder* / metabolism
  • Autism Spectrum Disorder* / pathology
  • Autism Spectrum Disorder* / physiopathology
  • Basolateral Nuclear Complex* / metabolism
  • Basolateral Nuclear Complex* / pathology
  • Basolateral Nuclear Complex* / physiopathology
  • Behavior, Animal*
  • Endocannabinoids / metabolism*
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / metabolism
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism
  • Nucleus Accumbens* / metabolism
  • Nucleus Accumbens* / pathology
  • Nucleus Accumbens* / physiopathology
  • Social Behavior*


  • Endocannabinoids
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Shank3 protein, mouse