Mesophasic organization of GABA_Areceptors in hippocampal inhibitory synapse

Abstract

1Information processing in the brain depends on synaptic transmission and plasticity, which in 2 turn require specialized organization of neurotransmitter receptors and scaffolding proteins 3 within the postsynaptic density (PSD). However, how these molecules are organized in situ 4 remains largely elusive, limiting our mechanistic understanding of synaptic formation and 5 functions. Here, we have developed template-free classification of over-sampled sub-6 tomograms to analyze cryo-electron tomograms of hippocampal synapses, enabling us to 7 identify type-A γ-aminobutyric acid receptor (GABA A R) in inhibitory synapses and determine 8 its in situ structure at 19 Å resolution. We found that these receptors are organized 9 hierarchically: from GABA A R super-complexes with a fixed 11-nm inter-receptor distance but 10 variable relative angles, through semi-ordered two-dimensional receptor networks with 11 reduced Voronoi entropy, to mesophasic assembly with a sharp phase boundary. This 12 assembly aligns with condensates of postsynaptic scaffolding proteins and putative 13 presynaptic vesicle release sites. Such mesophasic self-organization may allow synapses to 14 achieve a "Goldilocks" state with a delicate balance between stability and flexibility, enabling 15both reliability and plasticity in information processing. 16 hierarchical organization of GABA A Rs within the PSD, establishing the structural basis for 44 synaptic transmission and plasticity. 45 46 Results 47

Trans-synaptic assemblies link synaptic vesicles and neuroreceptors

“…Further development of automated acquisition methods that addresses the difficulties in finding structures of interest should increase the number of particles and refine the identification of complexes. Previous visualizations of neurotransmitter receptors by conventional and cryo-ET of dissociated neuronal cultures [68,45,69] and recent advances in thinning vitrified samples [70] raise expectations that imaging synapses of intact neurons by cryo-ET will become routine. The previous work also showed the structural similarity between synaptosomes and synapses in neuronal cultures, and the importance of cryopreparation for molecular imaging of synapses [44,45,39,38], which in combination with the template-free detection and classification ( [40]) is uniquely suited for precise molecular localization and identification in complex systems.…”

Scaling in Colloidal and Biological Networks

“…Self-organizing critical behavior was reported by Liu et al [ 52 ] for the organization of brain GABA A receptors (these are receptors of γ-Aminobutyric acid or GABA, the major neurotransmitter). The mean size of receptor networks in a synapse followed a power-law distribution as a function of receptor concentration with the exponent 1.87 representing the fractal dimension of receptor networks.…”