Role of Neurotrophins in Synapse Formation

Introduction

The neurotrophins (“neuro” means nerve and “trophe” means nutrient)¹ are a family of soluble, basic growth factors which regulate neuronal development, maintenance, survival and death in the central and peripheral nervous systems². They include NGF, the first member of the family to be discovered, BDNF, NT3 and NT4/5. Their actions are mediated by two types of receptors: the Trk family, which matches each neurotrophin to its own receptor³, and p75^NTR which is a universal neurotrophin receptor⁴.

The neurotrophins have been shown to affect dendritic and axonal growth⁵, efficacy of synaptic transmission⁶. maturation of synaptic contacts, density of synaptic innervation⁷, and development of occular dominance columns in the visual cortex⁸. BDNF specifically has emerged as a central player in this arena and has been shown to be essential in establishing neuronal connectivity⁹, modulation of axon and dendritic branching¹⁰, increasing synaptic transmission efficacy¹¹, and influencing synaptic and network maturation¹².

Synapses are assymetric communication junctions formed between two neurons, or at the neuromuscular junction, between a neuron and a muscle cell. Chemical synapses enable cell to cell communication via secretion of neurotransmitter, whereas in the less abundant electrical synapases, signals are transmitted through gap junctions. Synapse asssembly begins when axons approach their targets and establish contact with dendritic arbors or soma of their target neuron¹³.

Neurotrophins and Formation of Functional Synapses

In order to postulate a connection between neurotrophins and formation of functional synapses, one of the first things to investigate is the effect of neurotrophins on the number of synapses. It has been shown that synaptic density is increased 2.5 fold in the superior cerv ical ganglion of transgenic mice overexpressing BDNF and is decreased in BDNF knockout mice⁷. Mice lacking TrkB and Trk C (the specific receptors for BDNF) also show decreased density of synapses¹⁴. Each neurotrophin has a specific effect: in cultured hippocampal neurons it has been found that BDNF induced the formation of both excitory and inhibitory synapses, whereas NT-3 induced the formation of only excitory synapses¹⁵.

The effect of neurotrophins on synapse numbermay reflect not only the production of new synapses, but the stabilization of existing ones. It has been found that axon terminals of TrkB and TrkC deficient mice have decreased density of synaptic vesicles, and a dramatic and specific downregulation of presynaptic proteins. This points to a role for neurotrophins in the development and maturation of synaptic structure by regulating the levels of some presynaptic proteins¹⁴.

After establishing that neurotrophins affect the number and stablility of synapses, it must be established that these are functional synapses, according to the electrophysiological criterion. The first direct evidence that the presence of neurotrophins was required for formation of functional synapses was shown in Lymnae neurons.¹⁶ It was shown that when juxtaposed in cell culture, excitory synapse formation beween a variety of presynaptic and postsynaptic neurons depends on extrinsic trophic factors, and that the effect was mediated by receptor tyrosine kinases, leaving no doubt that the neurotrophins are involved, although specific neurotrophins were not identified. At central glutameaergic synapses, BDNF promotes the transition of immature, electrically “silent“ synapses into mature synapses¹⁷.

The precise mechanisms of neurotrophin actions are being elucidated. The formation of the synapse is a complicated process with multiple possibilities for regulation at the biochemical and topographical levels. One of the points to be clarified is the precise location of the neurotrophin effect. The clustering of neurotransmitter containing vesicles at the presynaptic side of the synapse occurs during synapse formation¹⁸. BDNF specifically increased the number of synaptic vesicles docked at the presynaptic terminal of the active zone of CA1 pyramidal neurons in hippocampal slices¹⁹. On the other hand, in Lymnae neurons, the modulation of postsynaptic nicotinic acetylcholine receptors was sufficient to account for the trophic factor induced excitory synaptogenesis²⁰. Therefore, it seems that the action of neurotrophins can be both at the presynaptic or postsynaptic side of the synapse, since there is experimental evidence for both views. The effect of electrical activity on synaptogenesis is complex. According to the classic Hebb’s Rule excitory synapses that succesfully stimulate a postsynaptic neuron, or are active when the postsynaptic neuron is depolarized are selectively stabilized¹⁸. However, it has been shown that neurotrophins can promote the development of excitary and inhibitory synapses in the presence of Tetrodotoxin citrate (#T-550) (which blocks voltage-gated Na⁺ channels) indicating that neurotrophins do not require action potential invasion of the presynaptic terminal to promote the maturation of these synapses²¹.

Conclusion

It is clear that the neurotrophin family, acting through their specific Trk receptors are essential for the formation and maturity of synapses in the central and peripheral nervous systems. The precise mechanisms of their complex actions are being investigated in in vivo and in vitro models even at the level of the single cell. As we continue to unravel the multifaceted effects of this family of proteins we come closer to a full understanding of the marvelous workings of the nervous system.

References

1. Berninger, B. et al. (1999) Nature 201, 862.
2. Roux, P. et al. (2002) Prog. Neurobiol. 67, 203.
3. Klein, R. et al. (1991) Cell 66, 395.
4. Rodriguez-Tebar, A. et al. (1992) EMBO J. 11, 917.
5. Cabelli, R. et al. (1995) Science 267, 1662.
6. Wang, X. et al. (1997) Neuron 19, 825.
7. Causing, C. et al. (1997) Neuron 18, 257.
8. Cabelli, R. et al. (1997) Neuron 19, 63.
9. Petit, F. et al. (2202) Neuroendocrinology 75, 55.
10. Lom, B. et al. (2002) J. Neurosci. 22, 7639.
11. Lu, B. et al. (1999) Neurosci. Res. 58, 76.
12. Yamada, M. et al. (2002) J. Neurosci. 22, 7580.
13. Cohen-Cory, S. (2002) Science 298, 770.
14. Martinez, A. et al. (1998) J. Neurosci. 18, 7336.
15. Vicario-Abejon, C. et al. (1998) J. Neurosci. 18, 7256.
16. Hamakawa, T. et al. J. Neurosci. 19, 9306.
17. Itami, C. et al. (2000) Brain Res. 857, 141.
18. Levitan, I. and Kaczmarek, (1991) The Neuron, Oxford University Press.
19. Tyler, W. et al. (2001) J. Neurosci. 21, 4249.
20. Woodin, M. et al. (2002) J. Neurosci. 22, 505.
21. Vicario-Abejon, C. et al. (2002) Nat. Rev. Neurosci. 3, 965.