Department of Chemical Engineering and the Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, USA.
Department of Biology, Washington University in St Louis, Saint Louis, MO, USA.
J R Soc Interface. 2021 Sep;18(182):20210454. doi: 10.1098/rsif.2021.0454. Epub 2021 Sep 15.
In the suprachiasmatic nucleus (SCN), γ-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABA receptor subunits, often referred to as synaptic GABA (gamma subunit) and extra-synaptic GABA (delta subunit). To test the functional roles of these distinct GABA in regulating circadian rhythms, we developed a multicellular SCN model where we could separately compare the effects of manipulating GABA neurotransmitter or receptor dynamics. Our model predicted that blocking GABA signalling modestly increased synchrony among circadian cells, consistent with published SCN pharmacology. Conversely, the model predicted that lowering GABA receptor density reduced firing rate, circadian cell fraction, amplitude and synchrony among individual neurons. When we tested these predictions, we found that the knockdown of delta GABA reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABA densities could enhance synchrony, as opposed to increasing delta GABA densities. Overall, our model reveals how blocking GABA receptors can modestly increase synchrony, while increasing the relative density of gamma over delta subunits can dramatically increase synchrony. We hypothesize that increased gamma GABA density in the winter could underlie the tighter phase relationships among SCN cells.
在视交叉上核（SCN）中，γ-氨基丁酸（GABA）是一种主要的神经递质。GABA 可以通过两种类型的 GABA 受体亚基传递信号，通常称为突触 GABA（γ 亚基）和非突触 GABA（δ 亚基）。为了测试这些不同 GABA 在调节生物钟中的功能作用，我们开发了一种多细胞 SCN 模型，在该模型中，我们可以分别比较操纵 GABA 神经递质或受体动力学的影响。我们的模型预测，阻断 GABA 信号会适度增加生物钟细胞之间的同步性，这与已发表的 SCN 药理学一致。相反，该模型预测降低 GABA 受体密度会降低单个神经元的放电率、生物钟细胞分数、振幅和同步性。当我们验证这些预测时，我们发现 δ GABA 的敲低会降低 SCN 外植体中细胞时钟基因表达的振幅和同步性。该模型进一步预测，增加 γ GABA 密度可以增强同步性，而不是增加 δ GABA 密度。总的来说，我们的模型揭示了阻断 GABA 受体如何适度增加同步性，而增加 γ 相对于 δ 亚基的相对密度可以显著增加同步性。我们假设冬季 GABA 密度的增加可能是 SCN 细胞之间相位关系更加紧密的原因。
