Cajal-Retzius neurons (CRNs) are among the first-born neurons in the neocortex and are critically involved in cortical layering during their transient lifetime. The molecular mechanisms behind early death of CRNs are still unclear but apoptosis is regulated by neuronal activity. During early development, CRNs are embedded into immature circuits where they mostly receive GABAergic inputs. Through immunohistochemistry and high-resolution confocal imaging, we quantified GABAergic synapse localizations across cortical layers during development in early postnatal mice and compared the GABAergic profile of CRNs with pyramidal neurons. These data revealed a transient peak of synapses in the marginal zone at postnatal day 3-5 mostly targeting CRNs. Previous patch-clamp recordings showed that GABAergic stimulation produces depolarizing responses in CRNs. Thus, we analyzed expression levels of chloride transporters NKCC1 and KCC2 in genetically labeled CRNs (∆Np73Cre/+, Wnt3aCre/+, and BaxCKO∆Np73) through multiplexed FISH. We found that, in contrast to most neurons, CRNs fail to increase KCC2 expression with development and, therefore, maintain immature-like features throughout their lifetime. To address the functional integration of CRNs, we tested their responsivity to network activation or GABAA receptor stimulation with combined electrophysiology and c-Fos immunostainings. The results highlighted the GABAA receptor-mediated activation of CRNs. Furthermore, chronic treatment of organotypic cultures with the NKCC1 blocker bumetanide increased p73-positive CRNs survival rates, suggesting that the peculiar chloride homeostasis of CRNs and their GABAergic inputs play a significant role in their natural death.Funded by ERA-NET NEURON 2021 through BMBF/DLR (ROSSINI Project).