TRENDS in Neurosciences Vol.24 No.6 June 2001 http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. 319 News& Comment News& Comment News& Comment News& Comment News& Comment because trkB phosphorylation remains high, BDNF can trigger transcription of various genes that are involved in neuronal plasticity. These genes could encode for neurotransmitters, such as NPY. Upregulation of BDNF induced by seizures in the hippocampus might thus be part of endogenous processes that limit epileptogenesis by regulating long-term changes in plasticity. With respect to potential BDNF-related treatment of epilepsy, such long-term regulations should not be underscored. Sophie Reibel INSERM U433, Faculté de Médecine, Laënnec, Lyon, France. Antoine Depaulis* U398 INSERM, Faculté de Médecine, Strasbourg, France. *e-mail: Depaulis@Neurochem.u-strasbg.fr Yves Larmet IPCB, Université Louis Pasteur, Strasbourg, France. References 1 Binder, D.K. et al. (2001) BDNF and epilepsy: too much of a good thing? Trends Neurosci. 24, 47–53 2 Thoenen, H. (1995) Neurotrophins and neuronal plasticity. Science 270, 593–598 3 Larmet, Y. et al. (1995) Protective effects of brain- derived neurotrophic factor on the development of hippocampal kindling in the rat. NeuroReport 6, 1937–1941 4 Osehobo, P. et al. (1999) Brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling without affecting paired- pulse measures of neuronal inhibition in adult rats. Neuroscience 92, 1367–1375 5 Reibel, S.et al. (2000) Brain-derived neurotrophic factor delays hippocampal kindling in the rat. Neuroscience 100, 777–788 6 Frank, L. et al. (1997) Effects of BDNF infusion on the regulation of TrkB protein and message in adult rat brain. Exp. Neurol. 145, 62–70 7 Mamounas, L.A. et al. (2000) BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J. Neurosci. 20, 771–782 8 Reibel, S. et al. (2000) Overexpression of neuropeptide Y induced by brain-derived neurotrophic factor in the rat hippocampus is long lasting. Eur. J. Neurosci. 12, 595–605 9 Vezzani, A. et al. (1999) Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci. 14, 25–30 10 Lothman, E.W. et al. (1993) Rapid kindling with recurrent hippocampal seizures. Epilepsy Res. 14, 209–220 11 Binder, D.K. et al. (1999) Selective inhibition of kindling development by intraventricular administration of TrkB receptor body. J. Neurosci. 19, 1424–1436 Response: BDNF and epilepsy – the bad could turn out to be good We appreciate the response of Reibel et al. to our recent review 1 . 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 2 . Because chronic (and presumably supraphysiologic) infusion of BDNF downregulates trkB receptor protein and responsiveness 3,4 , we believe that their results are consistent with studies showing that BDNF inhibition using either trkB receptor bodies 5 or BDNF gene deletion 6 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 7 . Among other evidence, the fact that transgenic mice chronically overexpressing BDNF demonstrate increased excitability in hippocampus and entorhinal cortex 8 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 9 , trk receptor activation 7 and NPY immunoreactivity 10 following seizures lends support to such a mechanism. The question mark at the end of our title 1 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. Devin K. Binder* Dept of Neurological Surgery, University of California, San Francisco, CA 94110, USA. *e-mail: dbinder@itsa.ucsf.edu Susan D. Croll Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. Christine M. Gall Dept of Anatomy and Neurobiology, University of California, Irvine, CA 93697-4292, USA. Helen E. Scharfman CNRRR, Helen Hayes Hospital, West Haverstraw, NY 10993-1195, Depts of Pharmacology and Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. References 1 Binder, D.K. et al. (2001) BDNF and epilepsy: too much of a good thing? Trends Neurosci. 24, 47–53 2 Larmet, Y. et al. (1995) Protective effects of brain- derived neurotrophic factor on the development of hippocampal kindling in the rat. NeuroReport 6, 1937–1941 3 Frank, L. et al. (1996) BDNF downregulates neurotrophin responsiveness, trkB protein and trkB mRNA levels in cultured rat hippocampal neurons. Eur. J. Neurosci. 8, 1220–1230 4 Knusel, B. et al. (1997) Ligand-induced downregulation of trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons. Neuroscience 78, 851–862 5 Binder, D.K. et al. (1999) Selective inhibition of kindling development by intraventricular administration of trkB receptor body. J. Neurosci. 19, 1424–1436 6 Kokaia, M. et al. (1995) Suppressed epileptogenesis in BDNF mutant mice. Exp. Neurol. 133, 215–224 7 Binder, D.K. et al. (1999) Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. J. Neurosci. 19, 4616–4626 8 Croll, S.D. et al. (1999) Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex. Neuroscience 93, 1491–1506 9 Gall, C.M. et al. (1996) Cellular localization of BDNF protein after recurrent seizures in rat: evidence for axonal transport of the newly synthesized factor. Epilepsia 37 (Suppl. 5), 47 10 Marksteiner, J. et al. (1990) Neuropeptide Y biosynthesis is markedly induced in mossy fibers during temporal lobe epilepsy of the rat. Neurosci. Lett. 112, 143–148 News& Comment