Kasahara Y, Arime Y, Hall F S, Uhl G R, Sora I
Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Curr Mol Med. 2015;15(3):237-44. doi: 10.2174/1566524015666150330143613.
Dopamine transporter (DAT) knockout (KO) mice show numerous behavioral alterations, including hyperlocomotion, cognitive deficits, impulsivity and impairment of prepulse inhibition of the startle reflex (PPI), phenotypes that may be relevant to frontostriatal disorders such as schizophrenia. Dendritic spine changes of pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) are among the most replicated of findings in postmortem studies of schizophrenia. The mechanisms that account for dendritic changes in the DLPFC in schizophrenia are unclear. Here, we report basal spine density of pyramidal neurons in the medial prefrontal cortex (mPFC), the motor cortex, the CA1 region of the hippocampus, and the basolateral amygdala in DAT KO mice. Pyramidal neurons were visualized using DAT KO mice crossbred with a Thy1-GFP transgenic mouse line. We observed a significant decrease in spine density of pyramidal neurons in the mPFC and the CA1 region of the hippocampus in DAT KO mice compared to that in WT mice. On the other hand, no difference was observed in spine density of pyramidal neurons in the motor cortex or the basolateral amygdala between DAT genotypes. These results suggest that decreased spine density could cause hypofunction of the mPFC and the hippocampus, and contribute to the behavioral abnormalities observed in DAT KO mice, including cognitive deficits. This might suggest that aberrant dopaminergic signaling may trigger dystrophic changes in dendrites of hippocampal and prefrontocortical pyramidal neurons in schizophrenia.
多巴胺转运体（DAT）基因敲除（KO）小鼠表现出多种行为改变，包括活动亢进、认知缺陷、冲动性以及惊吓反射前脉冲抑制（PPI）受损，这些表型可能与精神分裂症等额颞叶障碍有关。在精神分裂症的尸检研究中，背外侧前额叶皮质（DLPFC）中锥体神经元的树突棘变化是最常被重复验证的发现之一。精神分裂症中DLPFC树突变化的机制尚不清楚。在此，我们报告了DAT基因敲除小鼠内侧前额叶皮质（mPFC）、运动皮质、海马CA1区和基底外侧杏仁核中锥体神经元的基础树突棘密度。使用与Thy1-GFP转基因小鼠品系杂交的DAT基因敲除小鼠来观察锥体神经元。我们观察到，与野生型（WT）小鼠相比，DAT基因敲除小鼠mPFC和海马CA1区锥体神经元的树突棘密度显著降低。另一方面，在不同DAT基因型之间，运动皮质或基底外侧杏仁核中锥体神经元的树突棘密度未观察到差异。这些结果表明，树突棘密度降低可能导致mPFC和海马功能减退，并导致DAT基因敲除小鼠出现行为异常，包括认知缺陷。这可能表明，异常的多巴胺能信号传导可能引发精神分裂症中海马和前额叶皮质锥体神经元树突的营养不良性变化。
