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dc.contributor.authorCohan, M
dc.contributor.authorKopelman, J
dc.contributor.authorYueh, H
dc.contributor.authorYueh, Z
dc.contributor.authorGreene, N
dc.contributor.authorHarris, A
dc.contributor.authorBalsam, P
dc.contributor.authorLeonardo, D
dc.contributor.authorKramer, Edgar
dc.contributor.authorVeenstra-VanderWeele, J
dc.contributor.authorAhmari, S
dc.date.accessioned2021-12-13T12:10:08Z
dc.date.issued2022-01-20
dc.identifier.issn1359-4184
dc.identifier.issn1476-5578
dc.identifier.urihttp://hdl.handle.net/10026.1/18464
dc.description.abstract

Obsessive-compulsive disorder (OCD) is a disabling condition that often begins in childhood. Genetic studies in OCD have pointed to SLC1A1, which encodes the neuronal glutamate transporter EAAT3, with evidence suggesting that increased expression contributes to risk. In mice, midbrain Slc1a1 expression supports repetitive behavior in response to dopaminergic agonists, aligning with neuroimaging and pharmacologic challenge studies that have implicated the dopaminergic system in OCD. These findings suggest that Slc1a1 may contribute to compulsive behavior through altered dopaminergic transmission; however, this theory has not been mechanistically tested. To examine the developmental impact of Slc1a1 overexpression on compulsive-like behaviors, we therefore generated a novel mouse model to perform targeted, reversible overexpression of Slc1a1 in dopaminergic neurons. Mice with life-long overexpression of Slc1a1 showed a significant increase in amphetamine (AMPH)-induced stereotypy and hyperlocomotion. Single-unit recordings demonstrated that Slc1a1 overexpression was associated with increased firing of dopaminergic neurons. Furthermore, dLight1.1 fiber photometry showed that these behavioral abnormalities were associated with increased dorsal striatum dopamine release. In contrast, no impact of overexpression was observed on anxiety-like behaviors or SKF-38393-induced grooming. Importantly, overexpression solely in adulthood failed to recapitulate these behavioral phenotypes, suggesting that overexpression during development is necessary to generate AMPH-induced phenotypes. However, doxycycline-induced reversal of Slc1a1/EAAT3 overexpression in adulthood normalized both the increased dopaminergic firing and AMPH-induced responses. These data indicate that the pathologic effects of Slc1a1/EAAT3 overexpression on dopaminergic neurotransmission and AMPH-induced stereotyped behavior are developmentally mediated, and support normalization of EAAT3 activity as a potential treatment target for basal ganglia-mediated repetitive behaviors.

dc.format.extent1515-1526
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoen
dc.publisherSpringer Nature [academic journals on nature.com]
dc.subjectAnimals
dc.subjectCompulsive Behavior
dc.subjectDopamine
dc.subjectDopaminergic Neurons
dc.subjectExcitatory Amino Acid Transporter 3
dc.subjectMice
dc.subjectObsessive-Compulsive Disorder
dc.subjectStereotyped Behavior
dc.titleDevelopmental impact of glutamate transporter overexpression on dopaminergic neuron activity and stereotypic behavior
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, N.I.H., Extramural
plymouth.author-urlhttps://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000744842900002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008
plymouth.issue3
plymouth.volume27
plymouth.publication-statusPublished
plymouth.journalMolecular Psychiatry
dc.identifier.doi10.1038/s41380-021-01424-3
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeEngland
dcterms.dateAccepted2021-10-27
dc.rights.embargodate2022-7-20
dc.identifier.eissn1476-5578
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1038/s41380-021-01424-3
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2022-01-20
rioxxterms.typeJournal Article/Review


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