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 GABA_A 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 GABA_A 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 GABA_A receptors. This strategy can be employed to explore the cell biology and neurophysiology of GABA_A 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.

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。