OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior

Isaac D. Zike, Muhammad O. Chohan, Jared M. Kopelman, Emily N. Krasnow, Daniel Flicker, Katherine M. Nautiyal, Michael Bubser, Christoph Kellendonk, Carrie K. Jones, Gregg Stanwood, Kenji Tanaka, Holly Moore, Susanne E. Ahmari, Jeremy Veenstra-VanderWeele

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCDlike grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.

Original languageEnglish
Pages (from-to)5719-5724
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number22
DOIs
Publication statusPublished - 2017 May 30

Fingerprint

Excitatory Amino Acid Transporter 3
Obsessive-Compulsive Disorder
Basal Ganglia
Amphetamine
Grooming
Genes
Locomotion
Excitatory Amino Acid Transporter 1
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Amino Acid Transport System X-AG
Dopamine D1 Receptors
Genetic Linkage
Immediate-Early Genes
Genetic Association Studies
Mesencephalon
Cysteine
Glutamic Acid
Dopamine

Keywords

  • Basal ganglia
  • Dopamine
  • EAAC1
  • Obsessive-compulsive disorder
  • Tourette

ASJC Scopus subject areas

  • General

Cite this

Zike, I. D., Chohan, M. O., Kopelman, J. M., Krasnow, E. N., Flicker, D., Nautiyal, K. M., ... Veenstra-VanderWeele, J. (2017). OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. Proceedings of the National Academy of Sciences of the United States of America, 114(22), 5719-5724. https://doi.org/10.1073/pnas.1701736114

OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. / Zike, Isaac D.; Chohan, Muhammad O.; Kopelman, Jared M.; Krasnow, Emily N.; Flicker, Daniel; Nautiyal, Katherine M.; Bubser, Michael; Kellendonk, Christoph; Jones, Carrie K.; Stanwood, Gregg; Tanaka, Kenji; Moore, Holly; Ahmari, Susanne E.; Veenstra-VanderWeele, Jeremy.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 22, 30.05.2017, p. 5719-5724.

Research output: Contribution to journalArticle

Zike, ID, Chohan, MO, Kopelman, JM, Krasnow, EN, Flicker, D, Nautiyal, KM, Bubser, M, Kellendonk, C, Jones, CK, Stanwood, G, Tanaka, K, Moore, H, Ahmari, SE & Veenstra-VanderWeele, J 2017, 'OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 22, pp. 5719-5724. https://doi.org/10.1073/pnas.1701736114
Zike, Isaac D. ; Chohan, Muhammad O. ; Kopelman, Jared M. ; Krasnow, Emily N. ; Flicker, Daniel ; Nautiyal, Katherine M. ; Bubser, Michael ; Kellendonk, Christoph ; Jones, Carrie K. ; Stanwood, Gregg ; Tanaka, Kenji ; Moore, Holly ; Ahmari, Susanne E. ; Veenstra-VanderWeele, Jeremy. / OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 22. pp. 5719-5724.
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abstract = "Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCDlike grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.",
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