Trends in Neurosciences
ReviewThe neurotrophin hypothesis for synaptic plasticity
Section snippets
The neurotrophin hypothesis
The NT hypothesis proposes that repetitive neuronal activity enhances the expression, secretion and/or actions of NTs at the synapse to modify synaptic transmission and connectivity (Fig. 1), and thus provides a connection between neuronal activity and synaptic plasticity. NTs can play either an instructive or permissive role in activity-dependent synaptic modification of developing and adult brains. In the instructive role, modification is a consequence of NTs acting at the synapse to directly
Neuronal activity regulates neurotrophin expression and secretion
It is well known that mRNAs encoding various NTs and their respective trk receptors are selectively expressed in different regions of the brain9. The notion that the expression of these proteins is linked to activity-dependent plasticity was prompted by the finding that transcription of NT genes is regulated by neuronal activity. For example, epileptogenic activation of glutamatergic synapses increased the expression of mRNAs encoding nerve growth factor (NGF) and brain-derived neurotrophic
Pre- and postsynaptic secretion of neurotrophins
An important question concerning the function of NTs in synaptic plasticity is whether they are released from pre- or postsynaptic cells. Neurotrophins could be transported anterogradely from the soma to presynaptic terminals, released as a consequence of neuronal spiking, and received by the postsynaptic neuron. Conversely, neuronal or synaptic activity could lead to secretion of NTs from dendrites, and the secreted NTs might act as retrograde factors on the presynaptic neuron. Evidence now
Neurotrophins modulate synaptic efficacy
For NTs to play an instructive role in activity-dependent synaptic modification, NT secretion should, by itself, promote synaptic modifications. Thus, exogenous application of NTs should be sufficient to elicit the effects associated with activity. Lohof et al.8 were the first to show that exogenous NTs can modify synaptic efficacy in Xenopus nerve–muscle cultures. Acute treatment of these cultures with BDNF or NT-3 increased the frequency of spontaneous quantal transmitter release (without
Pre- and postsynaptic modification by neurotrophins
The question of whether potentiation occurs pre- or postsynaptically has drawn the field of LTP into a long-lasting debate that has contributed substantially to the understanding of central synaptic transmission52. Will this be the case for NT-induced synaptic modification? Currently, most available evidence suggests presynaptic modifications following acute NT treatments. In Xenopus NMJs, BDNF and NT-3 increased the frequency but not the amplitude of mEPSCs (Refs 8,13,53,54). Similarly, in
Target specificity of neurotrophin-induced potentiation
Activity-dependent plasticity of synaptic transmission is determined by the phenotype of pre- and postsynaptic neurons. In the hippocampus, the same pattern of stimulation that potentiates glutamatergic transmission onto glutamatergic neurons fails to do so when the postsynaptic neuron is GABAergic57., 58., 59.. In addition, the identity of the postsynaptic target cell in neocortical slices determines whether a synapse undergoes paired-pulse facilitation or depression – two forms of short-term
Role of neurotrophins in LTP and LTD
Regardless of whether or not NTs affect basal synaptic transmission, there is solid evidence implicating NTs in activity-induced LTP and LTD at central synapses. For example, the induction of LTP at SC–CA1 synapses by tetanic stimulation is impaired in hippocampal slices from BDNF knockout mice46., 61., but can be rescued either by re-expression of BDNF in the slice via viral infection62, or by infusion of recombinant BDNF for a few hours46. These results strongly suggest that BNDF is involved
Activity-dependent actions of neurotrophins
NTs were shown to increase the length and complexity of the dendritic trees in cortical neurons72; however, this effect could be abolished if spiking, synaptic transmission, or L-type Ca21 channels were blocked73. Similarly, the ocular dominance shift induced by monocular deprivation can be prevented by NGF only in the presence of neuronal activity74. These observations suggest that NT-induced morphological changes require neuronal activity, but how neuronal activity affects NT-dependent
Concluding remarks
Overall, experimental observations support the NT hypothesis as described at the outset of this review. The evidence is summarized in the model illustrated in Fig. 2c, where: (1) synthesis and secretion of NTs are increased by neuronal activity; (2) NTs are secreted postsynaptically; (3) the action of NTs on presynaptic terminals is spatially restricted; (4) active glutamatergic terminals impinging onto glutamate-containing (but not GABA-containing) neurons are potentiated; and (5) GABAergic
Acknowledgements
The authors thank Benedikt Berninger for comments on this manuscript. This work is supported by a grant from NIH (NS 37831).
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