Response: BDNF and epilepsy - the bad could turn out to be good

We appreciate the response of Reibel et al. to our recent review 1xBDNF and epilepsy: too much of a good thing?. Binder, D.K. et al. Trends Neurosci. 2001; 24: 47–53Abstract | Full Text | Full Text PDF | PubMed | Scopus (213)See all References1. Their group has made important contributions to the literature; in particular, they have shown that chronic intrahippocampal infusion of brain-derived neurotrophic factor (BDNF) delays kindling development in the rat 2xProtective effects of brain-derived neurotrophic factor on the development of hippocampal kindling in the rat. Larmet, Y. et al. NeuroReport. 1995; 6: 1937–1941CrossRef | PubMedSee all References2. Because chronic (and presumably supraphysiologic) infusion of BDNF downregulates trkB receptor protein and responsiveness 3xBDNF downregulates neurotrophin responsiveness, trkB protein and trkB mRNA levels in cultured rat hippocampal neurons. Frank, L. et al. Eur. J. Neurosci. 1996; 8: 1220–1230CrossRef | PubMed | Scopus (127)See all References, 4xLigand-induced downregulation of trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons. Knusel, B. et al. Neuroscience. 1997; 78: 851–862CrossRef | PubMed | Scopus (92)See all References, we believe that their results are consistent with studies showing that BDNF inhibition using either trkB receptor bodies 5xSelective inhibition of kindling development by intraventricular administration of trkB receptor body. Binder, D.K. et al. J. Neurosci. 1999; 19: 1424–1436PubMedSee all References5 or BDNF gene deletion 6xSuppressed epileptogenesis in BDNF mutant mice. Kokaia, M. et al. Exp. Neurol. 1995; 133: 215–224CrossRef | PubMed | Scopus (171)See all References6 delays kindling development. It is not clear to us, therefore, that the ‘chronic inhibitory effects of BDNF’ to which Reibel et al. refer are as a result of BDNF-induced activation of downstream inhibitory genes, such as neuropeptide Y (NPY) (as suggested by Reibel et al.) or instead are a result of downregulation of endogenous trkB receptor protein and responsiveness. Indeed, their own observations regarding the effects of BDNF in the rapid kindling model (described in their letter) fit quite well with the idea that BDNF infusion has an initial pro-excitatory effect followed by longer-term downregulation of BDNF signaling observed as suppression of kindling. To resolve this question, it would be useful to know the level of trk receptor activation at various time points in their model, because seizures are known to increase trk receptor activation in an anatomically and temporally specific manner 7xImmunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. Binder, D.K. et al. J. Neurosci. 1999; 19: 4616–4626PubMedSee all References7. Among other evidence, the fact that transgenic mice chronically overexpressing BDNF demonstrate increased excitability in hippocampus and entorhinal cortex 8xBrain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex. Croll, S.D. et al. Neuroscience. 1999; 93: 1491–1506CrossRef | PubMed | Scopus (187)See all References8 and spontaneous seizures (S.D. Croll et al., unpublished) lends further support to the idea that the net effect of BDNF in vivo is pro-excitatory. As mentioned in our review, we agree with their contention that BDNF might activate downstream pro-inhibitory genes, such as neuropeptide Y (NPY), to limit excitability. Indeed, the striking similarity in anatomy and time course of BDNF immunoreactivity 9xCellular localization of BDNF protein after recurrent seizures in rat: evidence for axonal transport of the newly synthesized factor. Gall, C.M. et al. Epilepsia. 1996; 37: 47See all References9, trk receptor activation 7xImmunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. Binder, D.K. et al. J. Neurosci. 1999; 19: 4616–4626PubMedSee all References7 and NPY immunoreactivity 10xNeuropeptide Y biosynthesis is markedly induced in mossy fibers during temporal lobe epilepsy of the rat. Marksteiner, J. et al. Neurosci. Lett. 1990; 112: 143–148CrossRef | PubMed | Scopus (96)See all References10 following seizures lends support to such a mechanism.The question mark at the end of our title 1xBDNF and epilepsy: too much of a good thing?. Binder, D.K. et al. Trends Neurosci. 2001; 24: 47–53Abstract | Full Text | Full Text PDF | PubMed | Scopus (213)See all References1 was meant to underscore the fact that we do not fully understand the role of BDNF in epileptogenesis. Our primary goal was to generate interest in the clearly dramatic effects of BDNF on excitability and plasticity in a number of in vitro and in vivo epilepsy models.