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Cryo-electron Microscopy

Cryo-electron Microscopy

Conventional electron microscopy (EM) involves dehydration, fixation, and staining of biological samples, which distorts the native state of biological molecules and results in several artifacts. Also, the high-energy electron beam damages the sample and makes it difficult to obtain high-resolution images. These issues can be addressed using cryo-EM, which uses frozen samples and gentler electron beams. The technique was developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, for...

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Memory engram synapse 3D molecular architecture visualized by cryoCLEM-guided cryoET.

Charlie Lovatt¹, Thomas J O'Sullivan¹, Clara Ortega-de San Luis^2,3,4

¹Astbury Centre for Structural Biology, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.

Biorxiv : the Preprint Server for Biology

|January 20, 2025

Summary

Researchers visualized the 3D molecular structure of brain cell connections (synapses) involved in memory. This breakthrough reveals the intricate molecular details of engram cells, advancing our understanding of memory storage.

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Area of Science:

Neuroscience
Structural Biology
Molecular Biology

Background:

Memory storage involves physicochemical changes in engram cells, forming neuroanatomical circuits modified by experience.
Synaptic plasticity, the modification of synaptic communication, underlies memory formation at the molecular level.
The 3D molecular architecture of synapses within engram circuits remains largely uncharacterized.

Purpose of the Study:

To visualize the in-tissue 3D molecular architecture of engram synapses.
To investigate the molecular constituents of synapses associated with contextual fear memory in the mouse hippocampus.
To establish a methodological framework for studying molecular plasticity in memory circuits.

Main Methods:

Utilized engram labelling technology combined with cryogenic correlated light and electron microscopy (cryoCLEM).
Employed cryogenic electron tomography (cryoET) guided by cryoCLEM for high-resolution 3D imaging.
Analyzed the CA1 region of the mouse hippocampus to examine engram cell synapses.

Main Results:

Revealed the 3D molecular architecture of engram synapses within the CA1 region.
Observed structural diversity in macromolecular constituents and organelles in pre- and postsynaptic compartments and the synaptic cleft.
Identified variations in membrane protein clusters, synaptic vesicle occupancy, and F-actin copy number within engram synapses.

Conclusions:

The 'engram to tomogram' approach provides an unprecedented view of engram synapse molecular organization.
Demonstrated the feasibility of visualizing detailed molecular structures within functional memory circuits in situ.
Offers a novel methodological framework for investigating molecular plasticity mechanisms underlying memory encoding, storage, and recall.