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The Journal of Neuroscience, September 15, 1998, 18(18):7336-7350

TrkB and TrkC Signaling Are Required for Maturation and Synaptogenesis of Hippocampal Connections

Albert Martínez¹, Soledad Alcántara¹, Víctor Borrell¹, José A. Del Río¹, Joan Blasi², Raquel Otal¹, Narciso Campos³, Albert Boronat³, Mariano Barbacid^{4, 5}, Inmaculada Silos-Santiago^{5, 6}, and Eduardo Soriano¹

¹ Department of Animal and Plant Cell Biology, University of Barcelona, Barcelona 08028, Spain, ² Department of Cell Biology and Pathology, University of Barcelona, L'Hospitalet de Llobregat, Barcelona 08907, Spain, ³ Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain, ⁴ Centro Nacional de Investigaciones Oncológicas Carlos III, Instituto de Salud Carlos III, 28220 Majalahonda, Madrid, Spain, ⁵ Department of Molecular Oncology, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, and ⁶ Department of Neurobiology, Millennium Pharmaceuticals Inc., Cambridge, Massachusetts 02139-4815

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 in trkB (/) and trkC (/) 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 both trkB (/) and trkC (/) mice. In addition, electron microscopic analyses showed that trkB (/) and trkC (/) 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 in trkB (/) mice. We conclude that neither trkB nor trkC 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 CNS in vivo. The data also suggest that the genes encoding for synaptic proteins may be targets of TrkB and TrkC signaling pathways.

Key words: TrkB receptors; TrkC receptors; neurotrophic factors; mutant mice; neuronal connections; synaptogenesis; synaptic-associated proteins; hippocampus

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18187336-15$05.00/0

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