Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice
Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice
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DOI：
10.1073/pnas.0709419104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Guidotti, Alessandro
中科院分区：
文献类型：
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作者：
Agis-Balboa, Roberto C.;Pinna, Graziano;Guidotti, Alessandro
由锥体神经元合成的别孕烯醇酮（Allopregnanolone，ALLO）是GABA作用于表达特异性神经甾体结合位点的GABA（A）受体的有效正向别构调节剂。在大脑中，ALLO是由孕酮通过两种酶的顺序作用合成的：5 α-还原酶I型（5 α-RI）和3 α-羟基类固醇脱氢酶（3 α-HSD）。在皮质、海马和杏仁核中，这些酶共定位于主要的GABA能输出神经元中[Agis-Balboa RC，Pinna G，Zhubi A，Maloku E，Veldic M，Costa E，Guidotti A（2006）Proc Natl Acad Sci USA 103：14602-14607]，但它们在GABA能中间神经元中不可检测。采用RT-PCR和原位杂交技术，本研究比较了5 α-RI和3 α-HSD mRNA表达水平在组圈养和社会隔离的雄性小鼠4周。在这些社会隔离的小鼠中，5a-RI的mRNA表达在海马CA 3区的杏仁核能锥体神经元、齿状回颗粒细胞、基底外侧杏仁核的杏仁核能神经元和V/VI层额叶（前边缘、下边缘）皮质（FC）的杏仁核能锥体神经元中显著降低。相反，在CA 1锥体神经元，中央杏仁核神经元，锥体神经元的第II/III层FC，丘脑腹内侧核神经元，纹状体中棘和网状丘脑核神经元，5a-RI mRNA的表达没有改变。重要的是，3a-HSD mRNA表达不受长期社会隔离（Si）的影响。这些数据表明，在雄性小鼠中，Si 4周后，5 α-RI mRNA的表达，这是ALLO生物合成的限速步骤酶，是特异性下调在杏仁核从皮质和海马区会聚的海马锥体神经元。在社会隔离的小鼠中，这种下调可能导致行为障碍的出现，如焦虑，攻击和认知功能障碍。
Allopregnanolone (ALLO), synthesized by pyramidal neurons, is a potent positive allosteric modulator of the action of GABA at GABA(A) receptors expressing specific neurosteroid binding sites. In the brain, ALLO is synthesized from progesterone by the sequential action of two enzymes: 5 alpha-reductase type I (5 alpha-RI) and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD). In the cortex, hippocampus, and amygdala, these enzymes are colocalized in principal glutamatergic output neurons [Agis-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006) Proc Natl Acad Sci USA 103:14602-14607], but they are not detectable in GABAergic interneurons. Using RT-PCR and in situ hybridization, this study compares 5a-RI and 3a-HSD mRNA brain expression levels in group housed and in socially isolated male mice for 4 weeks. In these socially isolated mice, the mRNA expression of 5a-RI was dramatically decreased in hippocampal CA3 glutamatergic pyramidal neurons, dentate gyrus granule cells, glutamatergic neurons of the basolateral amygdala, and glutamatergic pyramidal neurons of layer V/VI frontal (prelimbic, infralimbic) cortex (FC). In contrast, 5a-RI mRNA expression failed to change in CA1 pyramidal neurons, central amygdala neurons, pyramidal neurons of layer II/III FC, ventromedial thalamic nucleus neurons, and striatal medium spiny and reticular thalamic nucleus neurons. Importantly, 3a-HSD mRNA expression was unchanged by protracted social isolation (Si). These data suggest that, in male mice, after 4 weeks of Si, the expression of 5 alpha-RI mRNA, which is the rate-limiting-step enzyme of ALLO biosynthesis, is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. In socially isolated mice, this down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.