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

Shonesy BC, Parrish WP, Haddad HK, Stephenson JR, Báldi R, Bluett RJ, Marks CR, Centanni SW, Folkes OM, Spiess K, Augustin SM, Mackie K, Lovinger DM, Winder DG, Patel S, Colbran RJ
Biol Psychiatry. 2018 84 (4): 304-315

PMID: 29458998 · PMCID: PMC6023784 · DOI:10.1016/j.biopsych.2017.11.036

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 D 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.

Copyright © 2018 Society of Biological Psychiatry. All rights reserved.

MeSH Terms (13)

Animals Arachidonic Acids Autism Spectrum Disorder Corpus Striatum Endocannabinoids Glycerides Mice Mice, Knockout Receptor, Adenosine A2A Receptors, Dopamine D1 Signal Transduction Social Behavior Synaptic Transmission

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