title: ReducedVglut2/Slc17a6Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption.
abstract: The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the humanVGLUT2gene exist, and this study shows that reducedVglut2/Slc17a6gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.
authors.affiliation: Department of Organismal Biology, Uppsala University , SE-752 36 Uppsala, Sweden.
authors.forename: Nadine
authors.identifier: 0000-0002-8701-2690
authors.initials: N
authors.lastname: Schweizer
authors.affiliation: Department of Organismal Biology, Uppsala University, SE-752 36 Uppsala, Sweden; Department of Neuroscience, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Thomas
authors.identifier: 0000-0001-9039-7707
authors.initials: T
authors.lastname: Viereckel
authors.affiliation: Department of Neuroscience, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Casey J A
authors.initials: CJ
authors.lastname: Smith-Anttila
authors.affiliation: Department of Neuroscience, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Nordenankar
authors.affiliation: Department of Organismal Biology, Uppsala University , SE-752 36 Uppsala, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Arvidsson
authors.affiliation: Faculty of Pharmacy, Université de Montréal , Montréal, QC H3T 1J4, Canada.
authors.forename: Souha
authors.initials: S
authors.lastname: Mahmoudi
authors.affiliation: Oramacell , 75006 Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Zampera
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Wärner Jonsson
authors.affiliation: Department of Chemistry, BMC - Analytical Chemistry and Neurochemistry, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.affiliation: Faculty of Pharmacy, Université de Montréal , Montréal, QC H3T 1J4, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lévesque
authors.affiliation: Department of Organismal Biology, Uppsala University , SE-752 36 Uppsala, Sweden.
authors.forename: Åsa
authors.identifier: 0000-0002-8739-9645
authors.initials: Å
authors.lastname: Konradsson-Geuken
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University , SE-751 24 Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Oramacell , 75006 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dumas
authors.affiliation: Department of Organismal Biology, Uppsala University , SE-752 36 Uppsala, Sweden.
authors.forename: Åsa
authors.identifier: 0000-0002-8713-070X
authors.initials: Å
authors.lastname: Wallén-Mackenzie
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D003216:Conditioning, Operant / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D019422:Dietary Sucrose / Q000008:administration & dosage; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005247:Feeding Behavior / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009042:Motivation / Q000502:physiology; D009043:Motor Activity / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D012646:Self Administration; D020531:Subthalamic Nucleus / Q000378:metabolism* / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000172:deficiency* / Q000235:genetics; D000097577:Homeobox Protein PITX2
chemical_list: D019422:Dietary Sucrose; D050483:Dopamine Plasma Membrane Transport Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2; D000097577:Homeobox Protein PITX2; C493477:Slc17a6 protein, mouse
keywords: dopamine; dynorphin; glutamate; rearing; reward; self-administration