Recent studies have suggested a role for neurotrophins in the growth and refinement of neural connections, in dendritic growth, and in activity-dependent adult plasticity. To unravel the role of endogenous neurotrophins in the development of neural connections in the CNS, we studied the ontogeny of hippocampal afferents intrkB (−/−) andtrkC (−/−) mice. Injections of lipophilic tracers in the entorhinal cortex and hippocampus of newborn mutant mice showed that the ingrowth of entorhinal and commissural/associational afferents to the hippocampus was not affected by these mutations. Similarly, injections of biocytin in postnatal mutant mice (P10–P16) did not reveal major differences in the topographic patterns of hippocampal connections.In contrast, quantification of biocytin-filled axons showed that commissural and entorhinal afferents have a reduced number of axon collaterals (21–49%) and decreased densities of axonal varicosities (8–17%) in bothtrkB (−/−) andtrkC (−/−) mice. In addition, electron microscopic analyses showed thattrkB (−/−) andtrkC (−/−) mice have lower densities of synaptic contacts and important structural alterations of presynaptic boutons, such as decreased density of synaptic vesicles. Finally, immunocytochemical studies revealed a reduced expression of the synaptic-associated proteins responsible for synaptic vesicle exocytosis and neurotransmitter release (v-SNAREs and t-SNAREs), especially intrkB (−/−) mice. We conclude that neithertrkB nortrkC genes are essential for the ingrowth or layer-specific targeting of hippocampal connections, although the lack of these receptors results in reduced axonal arborization and synaptic density, which indicates a role for TrkB and TrkC receptors in the developmental regulation of synaptic inputs in the CNSin vivo. The data also suggest that the genes encoding for synaptic proteins may be targets of TrkB and TrkC signaling pathways.

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.