γ-aminobutyric acidA receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development
γ-aminobutyric acidA receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development
复制标题
DOI：
10.1046/j.1471-4159.2001.00329.x
复制
发表时间：
2001-06-01
影响因子：
4.7
通讯作者：
Coulter, DA
中科院分区：
文献类型：
--
作者：
Brooks-Kayal, AR;Shumate, MD;Coulter, DA
在出生后的发育过程中，GABA的功能发生了深刻的变化。GABA(A)受体表达的变化被认为是造成GABA能功能差异的原因，但在单个发育中的神经元中，亚单位的变化如何与受体功能相关还没有确切的定义。在目前的研究中，我们将14种不同的GABA(A)受体亚单位mRNAs的表达与大鼠出生后发育过程中单个海马齿状回颗粒细胞中该受体的药理特性的变化联系起来。我们发现了GABA(A)受体亚单位mRNA表达的显著发育差异，包括α1、α4和γ2亚单位mRNA的表达在未成熟神经元中的表达比成年神经元低两倍以上，而在未成熟神经元中的表达则高出10倍。这些差异既与亚基蛋白水平的区域性变化有关，也与未成熟齿状颗粒细胞中GABA(A)受体功能的变化有关，包括锌的阻断率增加一倍，I型苯二氮类药物位点调节剂的增加降低三倍。此外，我们发现，在出生后发育过程中，GABA(A)受体锌敏感性的变化与齿状回中锌泡的丰度之间存在负相关。这些发现表明，在出生后发育过程中，GABA(A)受体功能的改变与亚单位表达的发育差异有关。
Profound alterations in the function of GABA occur over the course of postnatal development. Changes in GABA(A) receptor expression are thought to contribute to these differences in GABAergic function, but how subunit changes correlate with receptor function in individual developing neurons has not been defined precisely. In the current study, we correlate expression of 14 different GABA(A) receptor subunit mRNAs with changes in the pharmacological properties of the receptor in individual hippocampal dentate granule cells over the course of postnatal development in rat. We demonstrate significant developmental differences in GABA(A) receptor subunit mRNA expression, including greater than two-fold lower expression of alpha1-, alpha4- and gamma2-subunit mRNAs and 10-fold higher expression of alpha5-mRNA in immature compared with adult neurons. These differences correlate both with regional changes in subunit protein level and with alterations in GABA(A) receptor function in immature dentate granule cells, including two-fold higher blockade by zinc and three-fold lower augmentation by type-I benzodiazepine site modulators. Further, we find an inverse correlation between changes in GABA(A) receptor zinc sensitivity and abundance of vesicular zinc in dentate gyrus during postnatal development. These findings suggest that developmental differences in subunit expression contribute to alterations in GABA(A) receptor function during postnatal development.