Tueting Patricia, Doueiri Mohemed-Salim, Guidotti Alessandro, Davis John M, Costa Erminio
Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street Chicago, IL 60612, USA.
Neurosci Biobehav Rev. 2006;30(8):1065-77. doi: 10.1016/j.neubiorev.2006.04.001.
Reelin, a large glycoprotein secreted by telencephalic GABAergic neurons, plays an important role in neuronal guidance embryonically and in synaptic plasticity postnatally. The reeler heterozygous mouse (+/rl) appears superficially normal but has been of interest as an animal model for psychosis since the discovery that reelin is 50% down-regulated in postmortem psychotic brain. Brain abnormalities in +/rl are similar to psychotic brain and include a reduction in glutamic acid de carboxylase 67 (GAD67), dendritic arbors and spine density in cortex and hippocampus, and abnormalities in synaptic function including long-term potentiation (LTP). In spite of these abnormalities, behavioral abnormalities in +/rl are subtle and controversial. Recent findings indicate that the reelin (RELN) and GAD67 promoters are hypermethylated in GABAergic neurons of psychotic postmortem brain and that DNA methyltransferase 1 (DNMT1) is up-regulated. Hypermethlyation of RELN and GAD67 promoters can be induced by treating mice with methionine, and these mice display brain and behavioral abnormalities similar to +/rl. Thus, an animal model that combines genetic heterozygocity with epigenesis holds promise for understanding the role of Reelin down-regulation in psychosis.
Reelin是一种由端脑GABA能神经元分泌的大型糖蛋白，在胚胎期的神经元导向以及出生后的突触可塑性方面发挥着重要作用。Reeler杂合小鼠（+/rl）表面上看似正常，但自发现Reelin在死后精神病大脑中下调50%以来，它作为一种精神病动物模型备受关注。+/rl小鼠的大脑异常与精神病大脑相似，包括谷氨酸脱羧酶67（GAD67）减少、皮质和海马体中的树突分支和棘密度降低，以及包括长时程增强（LTP）在内的突触功能异常。尽管存在这些异常，但+/rl小鼠的行为异常并不明显且存在争议。最近的研究结果表明，在死后精神病大脑的GABA能神经元中，Reelin（RELN）和GAD67启动子发生了高甲基化，并且DNA甲基转移酶1（DNMT1）上调。用蛋氨酸处理小鼠可诱导RELN和GAD67启动子的高甲基化，这些小鼠表现出与+/rl小鼠相似的大脑和行为异常。因此，一种将基因杂合性与表观遗传学相结合的动物模型有望用于理解Reelin下调在精神病中的作用。
