title: Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4.
abstract: An orphan member of the solute carrier (SLC) family SLC10, SLC10A4 has been found to be enriched in midbrain and brainstem neurons and has been found to co-localize with and to affect dopamine (DA) homeostasis. We generated an SLC10A4 knockout mouse (Slc10a4(Δ/Δ)) using Cre-targeted recombination, and characterized behavioral measures of motor and cognitive function as well as DA and acetylcholine (ACh) levels in midbrain and brainstem. In agreement with previous studies, Slc10a4 mRNA was preferentially expressed in neurons in the brains of wild-type (Slc10a4(+/+)) mice and was enriched in dopaminergic and cholinergic regions. Slc10a4(Δ/Δ) mice had no impairment in motor function or novelty-induced exploratory behaviors but performed significantly worse in measures of spatial memory and cognitive flexibility. Slc10a4(Δ/Δ) mice also did not differ from Slc10a4(+/+) in measures of anxiety. High-performance liquid chromatography (HPLC) measures on tissue punches taken from the dorsal and ventral striatum reveal a decrease in DA content and a corresponding increase in the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), indicating an increase in DA turnover. Punches taken from the brainstem revealed a decrease in ACh as compared with Slc10a4(+/+) littermates. Together, these data indicate that loss of SLC10A4 protein results in neurotransmitter imbalance and cognitive impairment.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States.
authors.forename: E J
authors.initials: EJ
authors.lastname: Melief
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States.
authors.forename: J T
authors.initials: JT
authors.lastname: Gibbs
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States.
authors.forename: R G
authors.initials: RG
authors.lastname: Morgan
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States.
authors.forename: C D
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States.
authors.forename: T J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98104, United States; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98104, United States.
authors.forename: R D
authors.initials: RD
authors.lastname: Palmiter
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States. Electronic address: mdarvas@uw.edu.
authors.forename: M
authors.initials: M
authors.lastname: Darvas
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D007859:Learning Disabilities / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D065853:Spatial Learning / Q000502:physiology; D027981:Symporters; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C000601541:SLC10A4 protein, mouse; D027981:Symporters; D033921:Vesicular Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D000109:Acetylcholine; D004298:Dopamine
keywords: SLC10A4; acetylcholine; cognitive impairment; dopamine