Nanoscale 3D EM reconstructions reveal intrinsic mechanisms of structural diversity of chemical synapses

Yingguo, Zhu; Uytiepo, Marco; Bushong, Eric A.; Haberl, Matthias G.; Beutter, Elizabeth; Scheiwe, Frederieke; Zhang, Weiheng; Chang, Lyanne; Luu, Danielle; Chui, Brandon; Ellisman, Mark H.; Maximov, Anton

doi:10.1016/j.celrep.2021.108953

Cited by 15 publications

(9 citation statements)

References 96 publications

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“…The appearance of SP clusters likely reflects the elaboration and the stabilization of the spine apparatus (Perez‐Alvarez et al , 2020 ), that is, together with the presence of polyribosomes, predictive of activity‐dependent spine enlargement (Chirillo et al , 2019 ). In agreement with our results, a recent electron microscopy study performed in the intact hippocampus revealed that mushroom spines but not smaller protrusions (e.g., thin, stubby, or filopodial) exhibit higher volume and PSD size when contacted by TetTx + presynaptic terminals and more likely contained a spine apparatus (Zhu et al , 2021 ). The input‐specificity of SP recruitment upon activity perturbation is also supported by previous reports showing that high‐frequency stimulation in the dentate gyrus enhances SP immunoreactivity selectively in the corresponding stimulated layers (Yamazaki et al , 2008 ; de Solis et al , 2017 ).…”

Section: Discussionsupporting

confidence: 93%

miR‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity

et al. 2022

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Homeostatic synaptic plasticity is a process by which neurons adjust their synaptic strength to compensate for perturbations in neuronal activity. Whether the highly diverse synapses on a neuron respond uniformly to the same perturbation remains unclear. Moreover, the molecular determinants that underlie synapse‐specific homeostatic synaptic plasticity are unknown. Here, we report a synaptic tagging mechanism in which the ability of individual synapses to increase their strength in response to activity deprivation depends on the local expression of the spine‐apparatus protein synaptopodin under the regulation of miR‐124. Using genetic manipulations to alter synaptopodin expression or regulation by miR‐124, we show that synaptopodin behaves as a “postsynaptic tag” whose translation is derepressed in a subpopulation of synapses and allows for nonuniform homeostatic strengthening and synaptic AMPA receptor stabilization. By genetically silencing individual connections in pairs of neurons, we demonstrate that this process operates in an input‐specific manner. Overall, our study shifts the current view that homeostatic synaptic plasticity affects all synapses uniformly to a more complex paradigm where the ability of individual synapses to undergo homeostatic changes depends on their own functional and biochemical state.

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Section: Discussionsupporting

confidence: 93%

miR‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity

et al. 2022

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“…Our results are consistent with the lack of homeostatic modifications to overall synaptic AMPAR levels observed when purified TeNT was exogenously applied prior to and throughout synapse formation and maturation ( Harms and Craig, 2005 ). In contrast to the apparently smaller PSDs we observed, another study using mice expressing TeNT in excitatory principal neurons reported slightly increased PSD volumes at mushroom-type spines, measured by 3D electron microscopy (EM) ( Sando et al, 2017 ; Zhu et al, 2021 ). However, in agreement with our results, PSD volume was reduced at stubby, thin and filopodial spines ( Zhu et al, 2021 ).…”

Section: Discussioncontrasting

confidence: 96%

AMPA and GABAA receptor nanodomains assemble in the absence of synaptic neurotransmitter release

Ramsay

Gookin

Ramsey

et al. 2023

Front. Mol. Neurosci.

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Postsynaptic neurotransmitter receptors and their associated scaffolding proteins assemble into discrete, nanometer-scale subsynaptic domains (SSDs) within the postsynaptic membrane at both excitatory and inhibitory synapses. Intriguingly, postsynaptic receptor SSDs are mirrored by closely apposed presynaptic active zones. These trans-synaptic molecular assemblies are thought to be important for efficient neurotransmission because they concentrate postsynaptic receptors near sites of presynaptic neurotransmitter release. While previous studies have characterized the role of synaptic activity in sculpting the number, size, and distribution of postsynaptic SSDs at established synapses, it remains unknown whether neurotransmitter signaling is required for their initial assembly during synapse development. Here, we evaluated synaptic nano-architecture under conditions where presynaptic neurotransmitter release was blocked prior to, and throughout synaptogenesis with tetanus neurotoxin (TeNT). In agreement with previous work, neurotransmitter release was not required for the formation of excitatory or inhibitory synapses. The overall size of the postsynaptic specialization at both excitatory and inhibitory synapses was reduced at chronically silenced synapses. However, both AMPARs and GABAARs still coalesced into SSDs, along with their respective scaffold proteins. Presynaptic active zone assemblies, defined by RIM1, were smaller and more numerous at silenced synapses, but maintained alignment with postsynaptic AMPAR SSDs. Thus, basic features of synaptic nano-architecture, including assembly of receptors and scaffolds into trans-synaptically aligned structures, are intrinsic properties that can be further regulated by subsequent activity-dependent mechanisms.

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“…The postsynaptic calcium homeostasis of glutamatergic PNs as well as local translation in spines are thought to be regulated by a part of the SER network called the spine apparatus (SA) 53,54 . Curiously, many excitatory synapses lack the mitochondria and SA 38,55 , but the underlying reasons and the functional implications of this heterogeneity are poorly understood. Prior EM studies, including recent work from our group, raise the possibility that subcellular localization of these organelles is influenced by sensory stimuli.…”

Section: Resultsmentioning

confidence: 99%

“…Prior EM studies, including recent work from our group, raise the possibility that subcellular localization of these organelles is influenced by sensory stimuli. However, this notion is based on indirect observations in electrically stimulated brain slices and excitatory neurons whose glutamate secretion was permanently blocked in vivo throughout development 38,55 . We found that, regardless of sensory experience and neuronal activity source, the mitochondria were more likely to be anchored in MSBs than in SSBs.…”

Section: Resultsmentioning

confidence: 99%

“…Each stack contained ~200,000 synapses. To expedite image processing, we built a pipeline for automatic segmentation of subcellular structures with an enhanced version of the previously described cloud-based convolutional neural network, CDeep3M 37,38 . This deep learning AI platform was tailored for the retraining on manually segmented ground truth labels in Amazon Web Services (AWS) to generate accurate predictions of plasma membranes, axonal and dendritic shafts, nerve terminals, dendritic spines, postsynaptic densities (PSDs), and intracellular organelles (Figures 1J, 1K, S5, and S6).…”

Section: Reconstruction Of Excitatory Circuits In the Ca3-ca1 Pathwaymentioning

confidence: 99%

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Synaptic architecture of a memory engram in the mouse hippocampus

Uytiepo,

Zhu,

Bushong

et al. 2024

Preprint

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Memory engrams are formed through experience-dependent remodeling of neural circuits, but their detailed architectures have remained unresolved. Using 3D electron microscopy, we performed nanoscale reconstructions of the hippocampal CA3-CA1 pathway following chemogenetic labeling of cellular ensembles with a remote history of correlated excitation during associative learning. Projection neurons involved in memory acquisition expanded their connectomes via multi-synaptic boutons without altering the numbers and spatial arrangements of individual axonal terminals and dendritic spines. This expansion was driven by presynaptic activity elicited by specific negative valence stimuli, regardless of the co-activation state of postsynaptic partners. The rewiring of initial ensembles representing an engram coincided with local, input-specific changes in the shapes and organelle composition of glutamatergic synapses, reflecting their weights and potential for further modifications. Our findings challenge the view that the connectivity among neuronal substrates of memory traces is governed by Hebbian mechanisms, and offer a structural basis for representational drifts.

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Nanoscale 3D EM reconstructions reveal intrinsic mechanisms of structural diversity of chemical synapses

Cited by 15 publications

References 96 publications

miR‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity

miR‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity

AMPA and GABAA receptor nanodomains assemble in the absence of synaptic neurotransmitter release

Synaptic architecture of a memory engram in the mouse hippocampus

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