Constitutive and Synaptic Activation of GIRK Channels Differentiates Mature and Newborn Dentate Granule Cells
Constitutive and Synaptic Activation of GIRK Channels Differentiates Mature and Newborn Dentate Granule Cells
复制标题
DOI：
10.1523/jneurosci.0674-18.2018
复制
发表时间：
2018-07-18
影响因子：
5.3
通讯作者：
Overstreet-Wadiche, Linda
中科院分区：
文献类型：
--
作者：
Gonzalez, Jose Carlos;Epps, S. Alisha;Overstreet-Wadiche, Linda
齿状回中稀疏的神经活动是由抑制性GABA能中间神经元的强大网络与主要神经元（齿状颗粒细胞（GC））的低内在兴奋性相结合来加强的。虽然支配突触抑制的细胞和电路特性已被很好地研究，但对赋予低GC内在兴奋性的机制知之甚少。在这里，我们证明了完整的G蛋白介导的信号有助于特征性的低静息膜电位，区分成熟的齿状GCs从CA1锥体细胞和发展中的成人出生的GCs。在来自雄性和雌性小鼠的成熟GC中，完整的G蛋白信号传导强烈地降低了内在兴奋性，而G蛋白激活的内向整流钾通道2（GIRK2）的缺失增加了兴奋性并阻断了G蛋白信号传导对内在特性的影响。同样，GABAB受体（GABABRs）或GIRK通道的药理学操纵会改变内在兴奋性和GC尖峰行为。然而，成人出生的新GC缺乏功能性GIRK活性，在成熟数周后出现阶段性和组成性GABABR介导的GIRK信号传导。时相激活是中间神经元特异性的，主要由表达nNOS的中间神经元而不是表达小清蛋白或生长抑素的中间神经元引起。总之，这些结果表明，G蛋白信号传导有助于区分成熟和发育中的齿状GCs的内在兴奋性，并进一步表明，GIRK通道活性的晚期成熟准备将GABAB受体信号传导的早期发育功能转化为GABABR介导的抑制。
Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the principal neurons, the dentate granule cells (GCs). Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Here we demonstrate that intact G protein-mediated signaling contributes to the characteristic low resting membrane potential that differentiates mature dentate GCs from CA1 pyramidal cells and developing adult-born GCs. In mature GCs from male and female mice, intact G protein signaling robustly reduces intrinsic excitability, whereas deletion of G protein-activated inwardly rectifying potassium channel 2 (GIRK2) increases excitability and blocks the effects of G protein signaling on intrinsic properties. Similarly, pharmacological manipulation of GABAB receptors (GABABRs) or GIRK channels alters intrinsic excitability and GC spiking behavior. However, adult-born new GCs lack functional GIRK activity, with phasic and constitutive GABABR-mediated GIRK signaling appearing after several weeks of maturation. Phasic activation is interneuron specific, arising primarily from nNOS-expressing interneurons rather than parvalbumin-or somatostatin-expressing interneurons. Together, these results demonstrate that G protein signaling contributes to the intrinsic excitability that differentiates mature and developing dentate GCs and further suggest that late maturation of GIRK channel activity is poised to convert early developmental functions of GABAB receptor signaling into GABABR-mediated inhibition.