Postnatal expression pattern of HCN channel isoforms in thalamic neurons: relationship to maturation of thalamocortical oscillations.
Postnatal expression pattern of HCN channel isoforms in thalamic neurons: relationship to maturation of thalamocortical oscillations.
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丘脑神经元 HCN 通道异构体的出生后表达模式：与丘脑皮质振荡成熟的关系。
DOI：
10.1523/jneurosci.0689-09.2009
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发表时间：
2009-07-08
期刊：
影响因子：
--
通讯作者：
Budde T
中科院分区：
文献类型：
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作者：
Kanyshkova T;Pawlowski M;Meuth P;Dubé C;Bender RA;Brewster AL;Baumann A;Baram TZ;Pape HC;Budde T
超极化激活的环核苷酸门控阳离子通道是超极化激活内向电流的分子底物。由于丘脑内HCN通道的发育尚不清楚，我们结合电生理学、分子生物学、免疫组织化学、在体脑电记录和计算机模拟技术，检测了大鼠外侧膝状体外侧膝状体背侧区(DLGN)丘脑皮质中继(TC)神经元的HCN基因表达和iH特性，以及这种成熟的功能后果。TC神经元的记录显示，从出生后(P)3天到P106天，Ih密度增加了~6倍，伴随着显著改变的电流动力学、cAMP敏感性和稳态激活特性。组织水平的定量显示环磷酸腺苷(CAMP)在发育过程中显著下降。因此，在幼年而不是成年大鼠中，基础腺酰环化酶活性的阻断伴随着iH激活曲线的超极化移动。对HCN通道异构体的定量分析显示，随着HCN4相对丰度的降低，HCN1、2和4mRNA和蛋白的表达水平稳步上升。在一个简化的丘脑网络中的计算机模拟表明，节律性增量活动的出现，出现在P12的脑电中，不同地依赖于iH电导和不同发育状态下cAMP的调制。这些数据表明，ih密度的发育增加是由于三种hcn通道亚型表达的增加，并且ih的异构体组成和细胞内cAMP水平相互作用，决定ih的特性，从而使有节奏的慢波睡眠活动模式逐渐成熟。
Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are the molecular substrate of the hyperpolarization-activated inward current (Ih). Since the developmental profile of HCN channels in the thalamus is not well understood, we combined electrophysiological, molecular biology, immunohistochemical, EEG recordings in vivo, and computer modeling techniques to examine HCN gene expression and Ih properties in rat thalamocortical relay (TC) neurons in dorsal part of the lateral geniculate nucleus (dLGN) and the functional consequence of this maturation. Recordings of TC neurons revealed a ~6-fold increase in Ih density between postnatal day (P) 3 to P 106, which was accompanied by significantly altered current kinetics, cAMP-sensitivity, and steady-state activation properties. Quantification of tissue levels revealed a significant developmental decrease in cyclic AMP (cAMP). Consequently the block of basal adenylyl cyclase activity was accompanied by a hyperpolarizing shift of the Ih activation curve in young but not adult rats. Quantitative analyses of HCN channel isoforms revealed a steady increase of mRNA and protein expression levels of HCN1, 2 and 4 with reduced relative abundance of HCN4. Computer modeling in a simplified thalamic network indicated that the occurrence of rhythmic delta activity, which was present in the EEG at P12, differentially depended on Ih conductance and modulation by cAMP at different developmental states. These data indicate that developmental increases in Ih density results from increased expression of three HCN channel isoforms and that isoform composition and intracellular cAMP levels interact in determining Ih properties to enable progressive maturation of rhythmic slow-wave sleep activity patterns.