Effects of a null mutation of the gene beta catenin in dopamine neurons

在我们的实验室，我们最近开发了一种Cre-loxP转基因模型，可以特异性灭活中脑腹侧DA神经元中的&#946；-catenin KO小鼠。&#946；-catenin KO小鼠在预期的孟德尔无线电下出生。与同龄的对照组相比，成年小鼠的体重较低。体视细胞计数未显示&#946；-catenin KO小鼠黑质和腹侧被盖区酪氨酸羟化酶阳性神经元数量的差异。然而，行为学研究表明，缺乏-catenin的小鼠在新环境中过度活跃，尽管在昼夜运动活动模式中没有发现变化。为了评估DA在纹状体中的释放动力学，对&#946；-catenin KO小鼠和WT对照组的脑切片进行了快速扫描循环伏安记录。初步研究表明，与对照组相比，KO动物纹状体中DA释放增加。KO动物纹状体前啡肽（PDyn） mRNA水平显著升高，表明与纹状体投射通路相关的神经元活动增强，而前脑啡肽（PPE） mRNA水平保持不变。这些结果表明&#946；-catenin在多巴胺能神经传递的发展和维持中起重要作用。我们的实验室目前专注于阐明由-catenin消融介导的分子机制，导致观察到的行为和多巴胺能神经传递的变化。

In our laboratory, we recently developed a Cre-loxP transgenic model to specifically inactivate β-catenin in DA neurons of the ventral midbrain (β-catenin KO mice). β-catenin KO mice are born at expected Mendelian radios. Adult mice present lower body weight compared with age-matched controls. Stereological cell counts do not reveal differences in the number of tyrosine hydroxylase positive neurons in the substantia nigra and ventral tegmental area of β-catenin KO mice. However, behavioral studies showed that β-catenin deficient mice are hyperactive in a novel environment, although no changes were found in the circadian locomotor activity pattern. To assess the dynamics of DA release in the striatum, fast-scan cyclic voltammetric recordings were performed in brain slices obtained from β-catenin KO mice and WT controls. Preliminary studies showed an increase of DA release in the striatum of KO animals when compared to controls. Striatal prodynorphin (PDyn) mRNA levels were significantly elevated in KO animals, suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway, while preproenkephalin (PPE) mRNA levels remained unchanged. These results suggest β-catenin plays an essential role in the development and maintenance of dopaminergic neurotransmission. Our lab is currently focused on elucidating what molecular mechanisms, mediated by β-catenin ablation, result in the observed changes in behavior and dopaminergic neurotransmission.