Chemogenetic silencing reveals presynaptic Gi/o protein-mediated inhibition of developing hippocampal synchrony in vivo

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES iScience Pub Date : 2024-09-20 DOI:10.1016/j.isci.2024.110997

Jürgen Graf, Arash Samiee, Tom Flossmann, Knut Holthoff, Knut Kirmse

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Abstract

Recent advances in understanding how neuronal activity shapes developing brain circuits increasingly rely on G_i/o-dependent inhibitory chemogenetic tools (G_i-DREADDs). However, their mechanisms of action and efficacy in neurons with immature G_i/o signaling are elusive. Here, we express the G_i-DREADD hM4Di in glutamatergic telencephalic neurons and analyze its impact on CA1 pyramidal neurons in neonatal mice. Using acousto-optic two-photon Ca²⁺ imaging, we report that activation of hM4Di leads to a complete arrest of spontaneous synchrony in CA1 in vitro. We demonstrate that hM4Di does not cause somatic hyperpolarization or shunting but rather mediates presynaptic silencing of glutamatergic neurotransmission. In vivo, inhibition through hM4Di potently suppresses early sharp waves (eSPWs) and discontinuous oscillatory network activity in CA1 of head-fixed mice before eye opening. Our findings provide insights into the role of G_i/o signaling in synchronized activity in the neonatal hippocampus and bear relevance for applying chemogenetic silencing at early developmental stages.

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化学基因沉默揭示突触前Gi/o蛋白介导的体内海马同步发育抑制作用

最近，在了解神经元活动如何塑造发育中的大脑回路方面取得的进展越来越多地依赖于依赖 Gi/o 的抑制性化学遗传工具（Gi-DREADDs）。然而，它们在Gi/o信号尚未成熟的神经元中的作用机制和功效尚不明确。在这里，我们在谷氨酸能端脑神经元中表达了 Gi-DREADD hM4Di，并分析了它对新生小鼠 CA1 锥体神经元的影响。通过声光双光子 Ca2+ 成像，我们报告了 hM4Di 的激活会导致 CA1 体外自发同步的完全停止。我们证明，hM4Di 不会导致体细胞超极化或分流，而是介导突触前谷氨酸能神经传递的沉默。在体内，通过 hM4Di 的抑制作用可有效抑制睁眼前头固定小鼠 CA1 中的早期尖波（eSPWs）和不连续振荡网络活动。我们的研究结果让我们深入了解了Gi/o信号在新生儿海马同步活动中的作用，并对在早期发育阶段应用化学基因沉默法具有重要意义。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

期刊介绍： Science has many big remaining questions. To address them, we will need to work collaboratively and across disciplines. The goal of iScience is to help fuel that type of interdisciplinary thinking. iScience is a new open-access journal from Cell Press that provides a platform for original research in the life, physical, and earth sciences. The primary criterion for publication in iScience is a significant contribution to a relevant field combined with robust results and underlying methodology. The advances appearing in iScience include both fundamental and applied investigations across this interdisciplinary range of topic areas. To support transparency in scientific investigation, we are happy to consider replication studies and papers that describe negative results. We know you want your work to be published quickly and to be widely visible within your community and beyond. With the strong international reputation of Cell Press behind it, publication in iScience will help your work garner the attention and recognition it merits. Like all Cell Press journals, iScience prioritizes rapid publication. Our editorial team pays special attention to high-quality author service and to efficient, clear-cut decisions based on the information available within the manuscript. iScience taps into the expertise across Cell Press journals and selected partners to inform our editorial decisions and help publish your science in a timely and seamless way.