Upregulation of BDNF mRNA and trkB mRNA in the Nigrostriatal System and in the Lesion Site Following Unilateral Transection of the Medial Forebrain Bundle J. L. Venero, M. L. Vizuete, M. Revuelta, C. Vargas,* J. Cano, andA. Machado Departamento de Bioquimica, Bromatologia y Toxicologia and *Departmento de Microbiologı ´a y Parasitologı ´a, Facultad de Farmacia, Universidad de Sevilla, Seville 41012, Spain Received February 22, 1998; accepted September 10, 1999 We have performed unilateral transection of the medial forebrain bundle (MFB) and studied BDNF mRNA and trkB mRNA levels at different postlesion times in the nigrostriatal system by means of in situ hybridization. BDNF mRNA levels were transiently induced in the substantia nigra pars compacta at 1 day postaxotomy. The disposition of BDNF mRNA express- ing cells at this postlesion time in substantia nigra mimicked that of the dopaminergic neurons express- ing the mRNA for the dopamine transporter. TrkB mRNA levels remained unaltered in the ventral mesen- cephalon at the different postlesion times examined—1 to 14 days. In contrast, trkB mRNA levels were signifi- cantly induced in the striatum at the longer postlesion time examined—14 days—when all neurodegenerative events are completed. It is becoming apparent that nigral BDNF mRNA levels are anterogradely trans- ported to its target tissue in striatum. However, follow- ing axotomy, the lesion site represents a second poten- tial target for BDNF action. Consequently, we also analyzed the pattern of mRNA expression for BDNF and trkB at the lesion site where dopaminergic axons are disconnected. There, we found notable inductions of both BDNF mRNA and trkB mRNA levels at 4 days postaxotomy. BDNF mRNA expressing cells were con- fined at the site of axotomy, which coincided precisely to that showing induction of trkB mRNA. Altogether, our results anticipate promising trophic roles of BNDF in the injured nigrostriatal system.  2000 Academic Press Key Words: axotomy; medial forebrain bundle; MFB; neurotrophins; brain-derived neurotrophic factor; sub- stantia nigra; striatum; trkB; injury; rat. INTRODUCTION Neurotrophic factors play key determinant roles in the regulation of development, neuronal survival, and adult nervous system plasticity (7, 10, 19). Many neurons within the adult brain require the presence of neurotrophins, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neu- rotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). The receptors for neurotrophins are formed by the tyrosine protein kinases trkA, trkB, and trkC and the previ- ously characterized low-affinity NGF receptor (p75LNGFR). While p75LNGFR binds all the neuro- trophins, trkA binds NGF, trkB binds BDNF, NT-4/5, and, with lower affinity, NT-3, while trkC only binds NT-3 (5, 8). BDNF is expressed in numerous areas of the CNS. Thus, BDNF mRNA and protein are present in the hippocampal formation, amygdala, thalamus neocor- tex, septum, and superior colliculus (13, 31, 37, 43), which is in accordance with a multipotent role for this neurotrophin in the CNS. In the nigrostriatal system, BDNF has been shown to stimulate the differentiation of mesencephalic dopamin- ergic neurons in vitro (24) and exposure of cultured dopaminergic neurons to this neurotrophin ameliorates the toxic effects of MPP + (6, 20). In vivo experiments have demonstrated that BDNF attenuates the loss of dopaminergic axons and prevents the rotational asym- metry induced by intrastriatal injections of 6-OHDA (26, 39, 44) and MPTP/MPP + (1, 18). The striatum, while lacking BDNF mRNA, contains BDNF protein at a level similar to that found in the hippocampal forma- tion (32). With these considerations, Altar and col- leagues have demonstrated that striatal BDNF is de- rived largely by anterograde transport of BDNF from substantia nigra and cortical neurons (3, 4), which sheds light on our understanding of how BDNF exerts its action in the normal and the injured nigrostriatal system. We previously performed a time-course analysis of cell death in the nigrostriatal system following unilat- eral transection of the medial forebrain bundle (MFB) (42) and found that most relevant changes were re- stricted to the first 5 days postlesion in terms of cell death. Axotomy will cease bidirectional BDNF traffick- ing between nigral dopaminergic cell bodies and stria- Experimental Neurology 161, 38–48 (2000) doi:10.1006/exnr.1999.7243, available online at http://www.idealibrary.com on 38 0014-4886/00 $35.00 Copyright  2000 by Academic Press All rights of reproduction in any form reserved.