INFLUENCE OF TEMPORAL ORIGIN ON DENTATE GRANULE NEURONS CONNECTIVITY

The dentate gyrus (DG) is a central hub of the hippocampus, acting as the main entry point for information. Its principal neurons, the dentate granule neurons (DGNs), reside in the granule cell layer (GCL), extend dendrites into the molecular layer (ML), and project axons toward CA3. DGNs are generated throughout life, making the DG a mosaic of neurons born at different times. Once considered similar upon maturation, these neurons differ in their position within the GCL and in dendritic and axonal architectures (Matthews et al., 2010; Kerloch et al., 2019; Mortessagne et al., in preparation), suggesting distinct connectivity patterns that remain unexplored.
Here, we investigated how DGNs born at different stages differ in synaptic connectivity. We tagged embryonically-born (E14) and early postnatally-born DGNs (P0) via in vivo electroporation, adolescent-born (P21) and adult-born DGNs (P84) via stereotaxic injections of modified retroviruses. We also employed transgenic mouse approaches.
Using CAG-GFP constructs, we found that later-born neurons exhibit higher spine density. FingR-based labelling of PSD95 and Gephyrin revealed differences in synaptic distribution. Later-born DGNs possess more excitatory PSD95⁺ synapses on dendrites—particularly in the inner ML—and at the soma. They also have more inhibitory Gephyrin⁺ synapses on dendrites, mainly in the outer ML, but fewer at the soma. Using expansion microscopy, we found that early-born neurons form fewer output contacts with thorny excrescences of pyramidal neurons but more with the dendritic shaft.

Together, these findings suggest that temporally distinct DGNs integrate into specialized neuronal circuits, likely supporting distinct functions in hippocampal processing.