Translational Profiling of Drd2-Expressing Populations Reveals Molecular Heterogeneity of Dentate Gyrus Mossy Cells along the Dorsoventral Axis

Abstract

Hilar mossy cells (MCs) are crucial for integrating and propagating signals across the hippocampal dorsoventral axis, mediating cognitive and affective processing. While MCs exhibit profound dorsoventral differences in their projections, physiology, and behavioral roles, the molecular basis underlying this functional specialization remains largely unexplored. To address this gap, we used translating ribosome affinity purification (TRAP) in male mice to systematically compare the translatome of Drd2-expressing, MC-enriched populations along the dorsoventral axis. This analysis revealed distinct translational signatures with 1,442 genes enriched in dorsal and 1,337 genes in ventral Drd2-expressing, MC-enriched populations. Pathway analysis demonstrated significant functional segregation along the dorsoventral axis. The dorsal population is notably enriched for genes linked to neuronal connectivity and synaptic transmission, whereas the ventral counterpart shows enrichment in genes associated with energy metabolism and cellular maintenance. Specifically, we identified a subset of dorsal enriched genes, including neurotransmitter receptors, ion channels, and axon guidance regulators, contrasting with ventral enriched genes highly related to glucose/fatty acid metabolism, oxidative phosphorylation, and exocytosis. We further predicted distinct sets of upstream transcriptional regulators activated in each subpopulation, providing insights into the regulatory networks that may drive molecular divergence. Our findings provide a translatomic basis for the dorsoventral heterogeneity of Drd2-expressing neurons that include MCs, offering molecular signatures associated with their differential contributions to hippocampal function.