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

doi:10.1016/j.biopsych.2017.11.036

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

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35 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 language	English (US)
Pages (from-to)	304-315
Number of pages	12
Journal	Biological psychiatry
Volume	84
Issue number	4
DOIs	https://doi.org/10.1016/j.biopsych.2017.11.036
State	Published - Aug 15 2018

Funding

This work was supported by National Institutes of Health (Grant Nos. K01 MH107765 to BCS, F31 MH106192 to RJB, R01 NS078291 to RJC, and K05 DA021696 to KM), the National Alliance for Research on Schizophrenia and Depression (Young Investigator Grant to RB), the Vanderbilt Kennedy Center (Hobbs Discovery Grant to DGW, SP, and RJC), and the National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (Project No. ZIA AA000416 to SMA and DML). Endocannabinoid measurements were conducted at the Vanderbilt Mass Spectrometry Research Center Facility and additional equipment support was received from the National Institutes of Health (Grant No. S10 OD017997 ). All behavioral testing was conducted at the Vanderbilt Neurobehavioral Core Facility. Drd1a-Cre and Adora2a-Cre mice were generated by The Gene Expression Nervous System Atlas Project, which was supported by the National Institute of Neurological Disorders and Stroke (Contract Nos. N01NS02331 and HHSN271200723701C to The Rockefeller University, New York, NY).

Keywords

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

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2017.11.036

Cite this

Shonesy, B. C., Parrish, W. P., Haddad, H. K., Stephenson, J. R., Báldi, R., Bluett, R. J., Marks, C. R., Centanni, S. W., Folkes, O. M., Spiess, K., Augustin, S. M., Mackie, K., Lovinger, D. M., Winder, D. G., Patel, S., & Colbran, R. J. (2018). Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Biological psychiatry, 84(4), 304-315. https://doi.org/10.1016/j.biopsych.2017.11.036

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title = "Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior",

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.",

keywords = "2-Arachindonoylglycerol, Autism spectrum disorder, Diacylglycerol lipase, Endocannabinoid, Nucleus accumbens, Striatum",

author = "Shonesy, {Brian C.} and Parrish, {Walker P.} and Haddad, {Hala K.} and Stephenson, {Jason R.} and Rita B{\'a}ldi and Bluett, {Rebecca J.} and Marks, {Christian R.} and Centanni, {Samuel W.} and Folkes, {Oakleigh M.} and Keeley Spiess and Augustin, {Shana M.} and Ken Mackie and Lovinger, {David M.} and Winder, {Danny G.} and Sachin Patel and Colbran, {Roger J.}",

note = "Publisher Copyright: {\textcopyright} 2018 Society of Biological Psychiatry",

year = "2018",

month = aug,

day = "15",

doi = "10.1016/j.biopsych.2017.11.036",

language = "English (US)",

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number = "4",

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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 2018, 'Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior', Biological psychiatry, vol. 84, no. 4, pp. 304-315. https://doi.org/10.1016/j.biopsych.2017.11.036

TY - JOUR

T1 - Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior

AU - Shonesy, Brian C.

AU - Parrish, Walker P.

AU - Haddad, Hala K.

AU - Stephenson, Jason R.

AU - Báldi, Rita

AU - Bluett, Rebecca J.

AU - Marks, Christian R.

AU - Centanni, Samuel W.

AU - Folkes, Oakleigh M.

AU - Spiess, Keeley

AU - Augustin, Shana M.

AU - Mackie, Ken

AU - Lovinger, David M.

AU - Winder, Danny G.

AU - Patel, Sachin

AU - Colbran, Roger J.

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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.

AB - 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.

KW - 2-Arachindonoylglycerol

KW - Autism spectrum disorder

KW - Diacylglycerol lipase

KW - Endocannabinoid

KW - Nucleus accumbens

KW - Striatum

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

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