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

Abstract

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 (Ϫ/Ϫ) and trkC (Ϫ/Ϫ) 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 (Ϫ/Ϫ) and trkC (Ϫ/Ϫ) mice. In addition, electron microscopic analyses showed that trkB (Ϫ/Ϫ) and trkC (Ϫ/Ϫ) 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 (Ϫ/Ϫ) 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.

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…Consistent with these observations, several groups report that BDNF treatment of hippocampal and cortical neuronal cultures increase synaptobrevin expression (Takei et al, 1997;Tartaglia et al, 2001;Yamada et al, 2002). In accordance with the effects of exogenous neurotrophins, mice that are deficient in either BDNF or TrkB exhibit marked reductions in the total number of docked vesicles at hippocampal synapses and a redistribution of docked vesicles to areas far from the active zone in the cerebellar synapses (Martinez et al, 1998;Pozzo-Miller et al, 1999;. Moreover, hippocampal sections from TrkB-deficient mice exhibit an overall reduction in syntaxin 1 and SNAP25 immunoreactivity (Martinez et al, 1998).…”

“…In accordance with the effects of exogenous neurotrophins, mice that are deficient in either BDNF or TrkB exhibit marked reductions in the total number of docked vesicles at hippocampal synapses and a redistribution of docked vesicles to areas far from the active zone in the cerebellar synapses (Martinez et al, 1998;Pozzo-Miller et al, 1999;. Moreover, hippocampal sections from TrkB-deficient mice exhibit an overall reduction in syntaxin 1 and SNAP25 immunoreactivity (Martinez et al, 1998). Consistent with reduced exocytotic machinery, TrkB-deficient mice exhibit impaired Ca 2+ -evoked glutamate and GABA release in cortical synaptosomal preparations from postnatal mice (Carmona et al, 2003).…”

Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression

“…By enhancing synaptic transmission and neuronal excitability, BDNF modulates synaptic change, including hippocampal long-term potentiation (LTP), a neural mechanism associated with learning and adaptive behaviours in adult animals (Poo 2001;Tyler et al 2002). BDNF-deficient mice show decreased synaptic innervation and reduced levels of synaptic vesicle proteins (Martinez et al 1998;Pozzo-Miller et al 1999), demonstrating that BDNF is important for normal synaptic signalling (Martinez et al 1998). Two potent stimuli that rapidly increase BDNF levels in the hippocampus are exercise and learning.…”

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

“…The observed changes in gene expression, e.g., enhanced expression of NT4 and diminished expression of trkB, may occur as a direct effect of TSC1 or TSC2 gene mutations or imply that changes in the expression of receptor might feedback to diminish expression of its ligand. Recent studies have suggested a role for neurotrophins in the growth and refinement of neural connections, 43 dendritic arborization, 17 programmed cell death, 44 cortical lamination, 18,45 synaptogenesis, 46 and in activity-dependent synaptic plasticity. 47,48 Altered expression of NT3, NT4, trkB, and trkC as well as netrin 1 may have numerous potentially deleterious effects on cortical lamination during development.…”