Effects of a null mutation of the tumor suppressor gene PTEN in dopamine neurons

Pten在小鼠中枢神经系统的缺失揭示了其在控制细胞大小和数量中的作用，从而为大头畸形和Lhermitte-Duclos病提供了令人信服的病因学。在本研究中，我们在一个有限的分化神经元群，即腹侧中脑的多巴胺神经元中删除了Pten。由此产生的突变小鼠目前正在我们的实验室进行研究。我们观察到黑质和VTA的神经元肥大。然而，通过运动活动测量，这种异常形态与急性和慢性可卡因暴露后的行为改变无关。此外，尽管多巴胺水平在幼鼠的纹状体中明显上调，但在纹状体中却保持不变。因此，我们的数据表明，多巴胺神经元中PTEN-PI3K/AKT通路的异常激活会增加该神经元群的数量和大小，但似乎不会改变纹状体中多巴胺的行为或分布。此外，在PTEN基因敲除的动物中，脑啡肽和去啡肽水平保持不变。在老年动物中进行研究将有必要确定PTEN消融是否对衰老过程中的多巴胺能系统神经元有害。

CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. In the present study, we deleted Pten in a limited differentiated neuronal population, the dopamine neurons of the ventral midbrain. Resulting mutant mice are currently under study in our laboratory. We observed neuronal hypertrophy in the substantia nigra and VTA. However, this abnormal morphology was not associated with behavioral changes after acute and chronic exposure to cocaine, as measured by locomotor activity. Also, while dopamine levels were clearly upregulated in the SN and VTA they remained unchanged in the striatum of young animals. Thus, our data suggest that abnormal activation of the PTEN-PI3K/AKT pathway in dopamine neurons increases the number and size of this neuronal population, but it does not appear to alter behavior or the distribution of dopamine in the striatum. Also, enkephaline and dynorphine levels remained unchanged in the PTEN knockout animals. Studies in aged animals will be necessary to determine if PTEN ablation is detrimental for the dopaminergic system neurons during aging.