Cajal-Retzius (CR) cells are transient neurons that control cortical lamination during development. Most CR cells disappear before birth, but a small population persists in the hippocampus postnatally for several months. In this study, Giulia Quattrocolo and colleagues investigate the role of postnatal CR cells in establishing the hippocampal network. First, the authors selectively ablate CR cells from the postnatal hippocampus by injecting a viral vector into a transgenic mouse line that specifically labels hippocampal CR cells. They then conduct morphological analysis on dendrite complexity and spine density, and observe impaired dendritic spine development in the CA1 pyramidal cells — the main output neurons of the hippocampus and the postsynaptic targets of CR cells. In addition, the authors perform bulk mRNA sequencing and shotgun proteomics, and find that the ablation of CR cells significantly alters the gene regulatory networks related to neuronal connectivity. More specifically, the authors find that the mRNA and protein levels of latrophilin 2, which is important for the establishment and maintenance of the hippocampal network, are significantly downregulated upon CR cell ablation. Overall, the findings suggest a crucial role for CR cells in the postnatal development of the hippocampal network.