Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4

• Slc10a4 expression is enriched in midbrain and brainstem regions.
• Slc10a4Δ/Δ mice have moderate impairment in spatial learning and cognitive flexibility.
• Dopamine and acetylcholine levels are reduced in Slc10a4Δ/Δ mice.

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 (Slc10a4Δ/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. Slc10a4Δ/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. Slc10a4Δ/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.