Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4.
Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4.
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DOI：
10.1016/j.neuroscience.2016.03.037
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发表时间：
2016-06-02
期刊：
影响因子：
3.3
通讯作者：
Darvas M
中科院分区：
文献类型：
--
作者：
Melief EJ;Gibbs JT;Li X;Morgan RG;Keene CD;Montine TJ;Palmiter RD;Darvas M
作为溶质载体家族SLC10的孤儿成员，SLC10A4已被发现在中脑和脑干神经元中富集，并被发现与多巴胺共定位并影响多巴胺稳态。我们使用Cre靶向重组方法生成了SLC10A4基因敲除小鼠（Slc10a4Δ/Δ），并表征了运动和认知功能以及中脑和脑干多巴胺和乙酰胆碱水平的行为测量。与以往的研究一致，Slc10a4 mRNA在野生型（Slc10a4+/+）小鼠的大脑神经元中优先表达，并在多巴胺能和胆碱能区域富集。Slc10a4Δ/Δ小鼠在运动功能或新奇性诱导的探索行为方面没有损伤，但在空间记忆和认知灵活性方面表现明显较差。Slc10a4Δ/Δ小鼠在焦虑测量方面也与Slc10a4+/+没有差异。对背侧纹状体和腹侧纹状体进行的高效液相色谱测量显示，多巴胺含量减少，代谢物DOPAC相应增加，表明多巴胺周转量增加。从脑干中取出的穿孔显示，与Slc10a4+/+幼崽相比，乙酰胆碱减少。综上所述，这些数据表明SLC10A4蛋白的缺失会导致神经递质失衡和认知障碍。
An orphan member of the solute carrier 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 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 dopamine and acetylcholine 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. HPLC measures on tissue punches taken from the dorsal and ventral striatum reveal a decrease in dopamine content and a corresponding increase in the metabolite DOPAC, indicating an increase in dopamine turnover. Punches taken from the brainstem revealed a decrease in acetylcholine as compared with Slc10a4+/+ littermates. Together, these data indicate that loss of SLC10A4 protein results in neurotransmitter imbalance and cognitive impairment.