Cortical layers VI to II develop between two layers of older neurons, the marginal and subplate zones, which are believed to have unique roles in cortical development While subplate cells have been found essential for the establishment of thalamocortical relationships, the function of the marginal zone and in particular of the neurons of CajalRetzius has not been elucidated. Here we show that an antibody against the calcium-binding protein calretinin labels the population of Cajal-Reizius cells throughout their life in the murine cerebral cortex. In prenatal and early postnatal stages, Cajal-Retzius cells were found evenly distributed throughout the murine cerebral cortex. Cajal-Retzius-like neurons were also found in the developing hippocampus and dentate gyrus, which indicates that they may have a general function in cortical development From P8 onward Cajal-Retzius cells disappeared from the neocortex and hippocampus, at the same time as degenerating immunoreactive neurons were observed. Calretinin-positive Cajal-Retzius cells were glutamate immunoreactive and their presumed axon terminals formed asymmetric synapses. These observations indicate that Cajal-Reizius cells may provide a tonic excitatory input, essential for the maturation of cortical neurons. Furthermore, since neuronal migration has been shown to be dependent on glutamate receptors, we propose that Cajal-Retzius cells releasing glutamate may direct migrating neuroblasts toward the marginal lamina, therefore creating the “inside-out” sequence of cortical development.

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