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Interrogating the function of GABAA receptors in the brain with optogenetic pharmacology
Current Opinion in Pharmacology ( IF 4.0 ) Pub Date : 2022-03-08 , DOI: 10.1016/j.coph.2022.102198
Richard H Kramer 1 , Rajit Rajappa 1
Affiliation  

To better understand neural circuits and behavior, microbial opsins have been developed as optogenetic tools for stimulating or inhibiting action potentials with high temporal and spatial precision. However, if we seek a more reductionist understanding of how neuronal circuits operate, we also need high-resolution tools for perturbing the function of synapses. By combining photochemical tools and molecular biology, a wide variety of light-regulated neurotransmitter receptors have been developed, enabling photo-control of excitatory, inhibitory, and modulatory synaptic transmission. Here we focus on photo-control of GABAA receptors, ligand-gated Cl channels that underlie almost all synaptic inhibition in the mammalian brain. By conjugating a photoswitchable tethered ligand onto a genetically-modified subunit of the GABAA receptor, light-sensitivity can be conferred onto specific isoforms of the receptor. Through gene editing, this attachment site can be knocked into the genome, enabling photocontrol of endogenous GABAA receptors. This strategy can be employed to explore the cell biology and neurophysiology of GABAA receptors. This includes investigating how specific isoforms contribute to synaptic and tonic inhibition and understanding the roles they play in brain development, long-term synaptic plasticity, and learning and memory.



中文翻译:

用光遗传学药理学研究大脑中 GABAA 受体的功能

为了更好地理解神经回路和行为,微生物视蛋白已被开发为光遗传学工具,用于以高时间和空间精度刺激或抑制动作电位。然而,如果我们寻求对神经元回路如何运作的更简化的理解,我们还需要高分辨率工具来扰乱突触的功能。通过结合光化学工具和分子生物学,已经开发出多种光调节神经递质受体,能够对兴奋性、抑制性和调节性突触传递进行光控制。在这里,我们专注于 GABA A受体的光控制,配体门控 Cl -哺乳动物大脑中几乎所有突触抑制的基础通道。通过将可光开关的束缚配体缀合到 GABA A受体的基因修饰亚基上,可以将光敏感性赋予受体的特定同种型。通过基因编辑,可以将这个附着位点敲入基因组,从而实现对内源性GABA A受体的光控制。该策略可用于探索 GABA A受体的细胞生物学和神经生理学。这包括研究特定亚型如何促进突触和强直抑制,并了解它们在大脑发育、长期突触可塑性以及学习和记忆中所起的作用。

更新日期:2022-03-08
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