TRKB AND TRKC SIGNALING ARE REQUIRED FOR MATURATION AND SYNAPTOGENESIS OF HIPPOCAMPAL CONNECTIONS

Recent studies have suggested a role for neurotrophins in the growth a nd refinement of neural connections, in dendritic growth, and in activ ity-dependent adult plasticity. To unravel the role of endogenous neur otrophins in the development of neural connections in the CNS, we stud ied the ontogeny of hippocampal afferents in trkB (-/-) and trkC (-/-) mice. Injections of lipophilic tracers in the entorhinal cortex and h ippocampus of newborn mutant mice showed that the ingrowth of entorhin al and commissural/associational afferents to the hippocampus was not affected by these mutations. Similarly, injections of biocytin in post natal mutant mice (P10-P16) did not reveal major differences in the to pographic patterns of hippocampal connections. In contrast, quantifica tion of biocytin-filled axons showed that commissural and entorhinal a fferents have a reduced number of axon collaterals (21-49%) and decrea sed densities of axonal varicosities (8-17%) in both trkB (-/-) and tr kC (-/-) mice. In addition, electron microscopic analyses showed that trkB (-/-) and trkC (-/-) mice have lower densities of synaptic contac ts and important structural alterations of presynaptic boutons, such a s decreased density of synaptic vesicles. Finally, immunocytochemical studies revealed a reduced expression of the synaptic-associated prote ins responsible for synaptic vesicle exocytosis and neurotransmitter r elease (v-SNAREs and t-SNAREs), especially in trkB (-/-) mice. We conc lude that neither trkB nor trkC genes are essential for the ingrowth o r layer-specific targeting of hippocampal connections, although the la ck of these receptors results in reduced axonal arborization and synap tic density, which indicates a role for TrkB and TrkC receptors in the developmental regulation of synaptic inputs in the CNS in vivo. The d ata also suggest that the genes encoding for synaptic proteins may be targets of TrkB and TrkC signaling pathways.