Krueger-Burg Dilja
Laboratory of Cell Biology and Neuroscience, Institute of Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
Trends Neurosci. 2025 Jan;48(1):47-61. doi: 10.1016/j.tins.2024.11.007. Epub 2025 Jan 8.
Despite the substantial contribution of disruptions in GABAergic inhibitory neurotransmission to the etiology of psychiatric, neurodevelopmental, and neurodegenerative disorders, surprisingly few drugs targeting the GABAergic system are currently available, partly due to insufficient understanding of circuit-specific GABAergic synapse biology. In addition to GABA receptors, GABAergic synapses contain an elaborate organizational protein machinery that regulates the properties of synaptic transmission. Until recently, this machinery remained largely unexplored, but key methodological advances have now led to the identification of a wealth of new GABAergic organizer proteins. Notably, many of these proteins appear to function only at specific subsets of GABAergic synapses, creating a diversity of organizer complexes that may serve as circuit-specific targets for pharmacotherapies. The present review aims to summarize the methodological developments that underlie this newfound knowledge and provide a current overview of synapse-specific GABAergic organizer complexes, as well as outlining future avenues and challenges in translating this knowledge into clinical applications.
尽管γ-氨基丁酸（GABA）能抑制性神经传递功能紊乱对精神疾病、神经发育障碍和神经退行性疾病的病因学有重大影响，但令人惊讶的是，目前针对GABA能系统的药物很少，部分原因是对特定回路的GABA能突触生物学了解不足。除了GABA受体，GABA能突触还包含一套复杂的组织蛋白机制，该机制调节突触传递的特性。直到最近，这套机制在很大程度上仍未被探索，但关键的方法学进展现已导致大量新的GABA能组织蛋白被鉴定出来。值得注意的是，这些蛋白中的许多似乎仅在GABA能突触的特定亚群中发挥作用，从而形成了多种组织蛋白复合物，这些复合物可能成为药物治疗的特定回路靶点。本综述旨在总结构成这一新知识基础的方法学进展，提供突触特异性GABA能组织蛋白复合物的当前概述，并概述将这一知识转化为临床应用的未来途径和挑战。
