Trends in Neurosciences
ReviewBDNF and epilepsy: too much of a good thing?
Section snippets
BDNF signal transduction
BDNF is a member of the neurotrophin family of neurotrophic factors, which also includes NGF, NT-3, NT-4/5 and NT-6. NTs bind with high affinity, but differing specificity, to NT receptors (trkA, trkB and trkC) and each NT binds with low affinity to the p75 receptor. Trk proteins are transmembrane receptor tyrosine kinases (RTKs) homologous to other RTKs, such as the epidermal growth factor (EGF) receptor and insulin receptor family 5. Signaling by RTKs is known to involve ligand-induced
BDNF effects in vitro
The classical view of NT function includes effects on the growth and survival of neurons during development. BDNF, in particular, appears to regulate neuronal morphology and synaptogenesis and have neuroprotective effects in diverse areas of the CNS 8. Whereas the functions of NTs in the adult brain are less clear, they might include neuroprotective and morphological effects following pathologic upregulation in response to seizures 4. However, little direct evidence exists to support such
Localization, transport and release of BDNF
BDNF mRNA has a widespread distribution in the CNS 23. Similarly, mRNA encoding the high affinity receptor for BDNF, trkB, is located throughout the brain 24., 25.. Notably, high levels of BDNF and trkB mRNA expression are found in brain areas that have been associated with seizure susceptibility, such as hippocampus and entorhinal cortex 4 (Fig. 1a). Within hippocampus, the granule cells, pyramidal cells and some hilar GABAergic neurons express mRNA encoding BDNF and trkB.
BDNF protein
BDNF upregulation by seizure activity
Seizures have been shown to stimulate the expression of a variety of genes, including those that encode transcription factors 32., 33., neuropeptides 34, growth associated proteins (GAP-43; 35), proteases 36 and also NTs and trk receptors. In particular, BDNF, NGF and trkB mRNA concentrations are increased in kindling and other seizure models, whereas NT-3 mRNA concentrations are decreased 3., 24., 37., 38., 39.. The magnitude of increase for BDNF mRNA is greatest in the hippocampus, being
Effects of inhibition of BDNF/trkB in seizure models
Evidence that BDNF is upregulated by seizures and positively modulates neuronal excitability within hippocampus suggests that BDNF and possibly other NTs play a role in epileptogenesis. This view is supported by recent studies using the kindling model. In this model, repeated, focal application of initially subconvulsive electrical stimuli eventually results in intense focal and tonic–clonic seizures. Once established, this enhanced sensitivity to electrical stimulation persists throughout the
Activation of trk receptors after seizures
The work described above suggests that limiting activation of the trkB receptor inhibits epileptogenesis, but whether and where NT receptor activation occurs during epileptogenesis remained unclear. Because ligand-induced receptor tyrosine phosphorylation is essential for NT-induced cellular responses 5, receptor tyrosine phosphorylation seems a logical index of the level of biological NT activity. Using antibodies that selectively recognize the phosphorylated form of trk receptors
BDNF-induced hyperexcitability of the mossy fiber-CA3 synapse
Based on data from normal mature animals described above, one might speculate that BDNF upregulation in the adult brain could predispose certain areas to seizures or even cause seizures. Indeed, in adult rat hippocampal slices, exposure to BDNF can produce multiple discharges and spreading depression in area CA3 and the entorhinal cortex upon afferent stimulation 17 (Fig. 3a). Acute application of exogenous BDNF to hippocampal slices appears to preferentially enhance the efficacy of excitatory
Cellular model of BDNF-trkB interaction
The studies summarized above suggest that: (1) upregulation of BDNF mRNA, protein and receptor activation occurs during epileptogenesis; (2) this upregulation is functionally relevant to increased excitability; and (3) the hippocampus and closely associated limbic structures might be particularly important in the pro-epileptogenic effects of BDNF. These observations suggest the following cellular and molecular model of the actions of BDNF in promoting excitability in the hippocampus (Fig. 4).
Other effects of BDNF
Based on the known effects of BDNF, it is possible that trkB receptor activation could contribute to epileptogenesis not only via synaptic effects on excitability, but also by inducing changes in dendritic or axonal sprouting, synaptic morphology and synapse formation on a slower time scale. The most prominent synaptic reorganization known to occur in the epileptic brain is sprouting of the dentate granule cell mossy fibers 73. Interestingly, mossy fiber sprouting was greater in BDNF+/-
Concluding remarks
Just over 10 years ago, Gall and Isackson 2 discovered that limbic seizures upregulate the mRNA encoding NGF. In the past decade, much has been learned about the importance of NTs to epileptogenesis. Although the expression of many growth-related genes is altered by seizure activity, the upregulation of BDNF and activation of trk receptors appear to play a key role in the development of hyperexcitability in vitro and in vivo, in particular in the hippocampus via modulation of mossy fiber–CA3
Acknowledgements
We acknowledge the contributions of many investigators to this rapidly growing field that we were unable to cite owing to space constraints. This work was supported by the NIH.
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