Information processing in the brain depends on specialized organization of neurotransmitter receptors and scaffolding proteins within the postsynaptic density. However, how these molecules are organized in situ remains largely unknown. In this study, template-free classification of oversampled sub-tomograms was used to analyze cryo-electron tomograms of hippocampal synapses. We identified type-A GABA receptors (GABA_ARs) in inhibitory synapses and determined their in situ structure at 19-Å resolution. These receptors are organized hierarchically: from GABA_AR super-complexes with a preferred inter-receptor distance of 11 nm but variable relative angles, through semi-ordered, two-dimensional receptor networks with reduced Voronoi entropy, to mesophasic assembly with a sharp phase boundary. These assemblies likely form via interactions among postsynaptic scaffolding proteins and receptors and align with putative presynaptic vesicle release sites. Such mesophasic self-organization might allow synapses to achieve a ‘Goldilocks’ state, striking a balance between stability and flexibility and enabling plasticity in information processing.

大脑中的信息处理取决于突触后密度内神经递质受体和支架蛋白的专门组织。然而，这些分子如何原位组织仍然很大程度上未知。在这项研究中，过采样子断层扫描的无模板分类用于分析海马突触的冷冻电子断层扫描。我们在抑制性突触中鉴定了 A 型 GABA 受体 (GABA _A Rs)，并以 19 Å 分辨率确定了它们的原位结构。这些受体按层次组织：来自 GABA _AR 超复合物的优选受体间距离为 11 nm，但相对角度可变，通过半有序的二维受体网络，Voronoi 熵减少，形成具有尖锐相界的中间相组装。这些组件可能通过突触后支架蛋白和受体之间的相互作用形成，并与假定的突触前囊泡释放位点对齐。这种中间相自组织可能使突触达到“金发姑娘”状态，在稳定性和灵活性之间取得平衡，并在信息处理中实现可塑性。