In the suprachiasmatic nucleus (SCN), γ-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABA_A receptor subunits, often referred to as synaptic GABA_A (gamma subunit) and extra-synaptic GABA_A (delta subunit). To test the functional roles of these distinct GABA_A 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_A 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_A reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABA_A densities could enhance synchrony, as opposed to increasing delta GABA_A densities. Overall, our model reveals how blocking GABA_A 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_A 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）是主要的神经递质。 GABA 可以通过两种类型的 GABA _A受体亚基发出信号，通常称为突触 GABA _A （γ 亚基）和突触外 GABA _A （δ 亚基）。为了测试这些不同的 GABA _A在调节昼夜节律中的功能作用，我们开发了一个多细胞 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效果。我们的模型预测，阻断 GABA 信号传导会适度增加昼夜节律细胞之间的同步性，这与已发表的 SCN 药理学一致。相反，该模型预测降低 GABA _A受体密度会降低各个神经元之间的放电率、昼夜节律细胞分数、幅度和同步性。当我们测试这些预测时，我们发现 delta GABA _A的敲低降低了 SCN 外植体细胞间时钟基因表达的幅度和同步性。该模型进一步预测，增加 γ GABA _A密度可以增强同步性，而不是增加 delta GABA _A密度。总体而言，我们的模型揭示了阻断 GABA _A受体如何适度增加同步性，同时增加 γ 相对于 δ 亚基的相对密度如何显着增加同步性。我们假设冬季伽马 GABA _A密度增加可能是 SCN 细胞之间更紧密的相位关系的基础。