Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior

Brian C. Shonesy*, Walker P. Parrish, Hala K. Haddad, Jason R. Stephenson, Rita Báldi, Rebecca J. Bluett, Christian R. Marks, Samuel W. Centanni, Oakleigh M. Folkes, Keeley Spiess, Shana M. Augustin, Ken Mackie, David M. Lovinger, Danny G. Winder, Sachin Patel, Roger J. Colbran

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Background: Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored. Methods: Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D1 receptor–expressing or adenosine A2a receptor–expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in the ventral and dorsal striatum. Results: Targeted deletion of DGLα from direct-pathway MSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from indirect-pathway MSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct-pathway MSNs also led to increased glutamatergic drive, which is consistent with a loss of retrograde feedback inhibition. Subregional DGLα deletion from the dorsal striatum produced deficits in social interaction, whereas deletion from the ventral striatum resulted in repetitive grooming. Conclusions: These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.

Original languageEnglish (US)
Pages (from-to)304-315
Number of pages12
JournalBiological psychiatry
Volume84
Issue number4
DOIs
StatePublished - Aug 15 2018
Externally publishedYes

Keywords

  • 2-Arachindonoylglycerol
  • Autism spectrum disorder
  • Diacylglycerol lipase
  • Endocannabinoid
  • Nucleus accumbens
  • Striatum

ASJC Scopus subject areas

  • Biological Psychiatry

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