28 Feb 2024

Every connection counts

Researchers at the Ernst Strüngmann Institute (ESI) have succeeded for the first time in carrying out a large-scale 3D electron microscope analysis of the CA3 region in the hippocampus and showing how strongly the individual nerve cells are interconnected.

How does memory work, how do we retrieve information from memory and how do we learn? Researchers agree on one thing: the hippocampus plays an important role in this, especially a small subregion called CA3. However, the underlying mechanisms are still unclear.

A common theory assumes that the cells in the CA3 region are particularly well connected with each other and are therefore able to complete patterns, i.e. retrieve memories. However, more recent data had rejected this high level of connectivity, thus calling into question the established theory of intensive connectivity as a prerequisite for memory.

How is the network in CA3 actually organized? How strong or weak is the connectivity of the individual cells? Researchers at the Ernst Strüngmann Institute (ESI) and Charité Berlin decided to pursue a two-pronged approach: While the research group at Charité investigated the question using physiological measurements of functional connectivity, the researchers at ESI dedicated themselves to the detailed reconstruction of a mouse CA3 module using 3D electron microscopy. In doing so, they created the first connectomic analysis of the memory circuit in mammals. Both approaches were complemented by computer modeling.

Both investigations - the electrophysiological measurements at the Charité and the structural 3D electron microscopy at the ESI - revealed a connection rate of around 10 percent, that is ten times higher than what was last reported. These results strengthen the theory that memory and learning are based on strong connectivity; and at the same time refute models that assume a weak connection rate as a basis.

The detailed mapping of the connections between pyramidal cells in CA3, which has now been achieved for the first time at the ESI, is extremely difficult and time-consuming. Mourat Vezir, first author for electron microscopy, is all the more pleased: “When we were finally able to reconstruct these wonderful nerve cells and their connections, it was incredibly fascinating.” Mapping the CA3 is only the first step. “In the long term, we want to understand the entire circuitry in the hippocampus,” says Helene Schmidt, head of the research group at the ESI. “We are very happy that the analysis of this small area has already provided such important insights into how the underlying mechanisms of our memory work.”

Original Publication
Sammons RP*, Vezir M*, Moreno-Velasquez L*, Cano G*, Orlando M, Sievers M, Grasso E, Metodieva VD, Kempter R, Schmidt H**, Schmitz D** (2024). Structure and function of the hippocampus CA3 module. PNAS 121 (6), e2312281120. https://doi.org/10.1073/pnas.2312281120 * equally contributing, ** shared correspondence