Expression of Brain-Derived Neurotrophic Factor and TrkB Neurotrophin Receptors after Striatal Injury in the Mouse

Brain-derived neurotrophic factor (BDNF) promotes the survival and differentiation of nigral dopaminergic neurons and supports the activity of dopaminergic cells grafted into the striatum. However, little attention has been given to the physiological role of endogenous BDNF and its receptor TrkB within the nigrostriatal dopamine system. We know that striatal injury is followed by long-term stimulation of dopaminergic activity in the striatum, could BDNF play a role in this phenomenon? One week after physical injury to the striatum of C57/Black mice, just before dopaminergic activation becomes obvious, in situ hybridization on coronal sections through mouse striatum reveals that BDNF mRNA expression increases significantly before returning to basal levels within 1 month. Expression of mRNA for TrkB follows a very different pattern. No change of expression of the full-length and catalytically competent TrkBTK+ receptor is seen. However, expression of the truncated form of the receptor TrkTK-, which lacks the catalytic tyrosine kinase domain, does increase and stays elevated for at least 2 months after injury. When combined with observations of dopaminergic activation after striatal injury and the neuroprotective effects of BDNF introduced into the striatum, our findings suggest that BDNF and TrkBTK- do indeed play a role in dopaminergic regeneration and repair.

[1]  J. Cadet,et al.  Sham transplantation protects against 6-hydroxydopamine-induced dopaminergic toxicity in rats: behavioral and morphological evidence , 1991, Brain Research.

[2]  D. Jacobowitz,et al.  Fetal nondopaminergic neural implants in parkinsonian primates. Histochemical and behavioral studies. , 1991, Journal of neurosurgery.

[3]  N. Lindefors,et al.  Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain , 1991, Experimental Neurology.

[4]  M. Huntsman,et al.  BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: Temporal patterns of induction distinct from NGF , 1991, Neuron.

[5]  H. Sawai,et al.  Brain-Derived Neurotrophic Factor and Neurotrophin-4/5 Stimulate Growth of Axonal Branches from Regenerating Retinal Ganglion Cells , 1996, The Journal of Neuroscience.

[6]  N. Belluardo,et al.  Increased expression of trkB and trkC messenger RNAS in the rat forebrain after focal mechanical injury , 1993, Neuroscience.

[7]  H. Hung,et al.  The mesolimbic dopaminergic pathway is more resistant than the nigrostriatal dopaminergic pathway to MPTP and MPP+ toxicity: role of BDNF gene expression. , 1996, Brain research. Molecular brain research.

[8]  O. Lindvall,et al.  Neurotrophins and brain insults , 1994, Trends in Neurosciences.

[9]  T. Hunter,et al.  trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors , 1991, Molecular and cellular biology.

[10]  P. Ernfors,et al.  Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system , 1992, Neuroscience.

[11]  M. Barbacid,et al.  The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain , 1990, Cell.

[12]  Brock L. Eide,et al.  Naturally Occurring Truncated trkB Receptors Have Dominant Inhibitory Effects on Brain-Derived Neurotrophic Factor Signaling , 1996, The Journal of Neuroscience.

[13]  D. Reis,et al.  The effect of forebrain lesions in the neonatal rat: Survival of midbrain dopaminergic neurons and the crossed nigrostriatal projection , 1983, The Journal of comparative neurology.

[14]  M. Barbacid,et al.  trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. , 1989, The EMBO journal.

[15]  O. Lindvall,et al.  Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis , 1991, Neuron.

[16]  R. Plunkett,et al.  Traumatized Rat Striatum Produces Neurite-Promoting and Neurotrophic Activitiesin Vitro , 1996, Experimental Neurology.

[17]  L. Olson,et al.  Localization of brain-derived neurotrophic factor mRNA to neurons in the brain by in situ hybridization , 1990, Experimental Neurology.

[18]  R MEYERS,et al.  Surgical experiments in the therapy of certain 'extrapyramidal' diseases: a current evaluation. , 1951, Acta psychiatrica et neurologica. Supplementum.

[19]  C. Shults,et al.  BDNF attenuates the effects of intrastriatal injection of 6-hydroxydopamine , 1995 .

[20]  T. H. Burnstine,et al.  Movement Disorders 2 , 1988, Neurology.

[21]  J. Kordower,et al.  Adrenal medullary autografts into the basal ganglia of Cebus monkeys: Injury-induced regeneration , 1988, Experimental Neurology.

[22]  P. Gluckman,et al.  Brain-derived neurotrophic factor is induced as an immediate early gene following N-methyl-d-aspartate receptor activation , 1993, Neuroscience.

[23]  P. Distefano,et al.  Differential distribution of exogenous BDNF, NGF, and NT‐3 in the brain corresponds to the relative abundance and distribution of high‐affinity and low‐affinity neurotrophin receptors , 1995, The Journal of comparative neurology.

[24]  G. Donnan,et al.  Dopaminergic responses to striatal damage , 1996, Journal of the Neurological Sciences.

[25]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[26]  F. Hefti,et al.  Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin 3. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Y. Agid,et al.  Does adrenal graft enhance recovery of dopaminergic neurons in Parkinson's disease? , 1990, Annals of neurology.

[28]  J. W. Taylor,et al.  Dimeric structure and conformational stability of brain-derived neurotrophic factor and neurotrophin-3. , 1992, Biochemistry.

[29]  S. Wiegand,et al.  Efficacy of Brain‐Derived Neurotrophic Factor and Neurotrophin‐3 on Neurochemical and Behavioral Deficits Associated with Partial Nigrostriatal Dopamine Lesions , 1994, Journal of neurochemistry.

[30]  H. Lagercrantz,et al.  Expression of members of the trk family in the developing postnatal rat brain. , 1993, Brain research. Developmental brain research.

[31]  F. Hefti,et al.  6-Hydroxydopamine lesions reduce BDNF mRNA levels in adult rat brain substantia nigra. , 1994, Neuroreport.

[32]  J. Cedarbaum,et al.  The Therapeutic Potential of Neurotrophic Factors in the Treatment of Parkinson's Disease , 1993, Experimental Neurology.

[33]  M. Radeke,et al.  Signal Transduction Mediated by the Truncated trkB Receptor Isoforms, trkB.T1 and trkB.T2 , 1997, The Journal of Neuroscience.

[34]  M. Barbacid.  The Trk family of neurotrophin receptors. , 1994, Journal of neurobiology.

[35]  M. Levivier,et al.  Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson's disease , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  G. Yancopoulos,et al.  BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra , 1991, Nature.

[37]  H. Phillips,et al.  Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons. , 1990, Science.

[38]  R. Penn,et al.  Putative chromaffin cell survival and enhanced host‐derived TH‐Fiber innervation following a functional adrenal medulla autograft for Parkinson's disease , 1991, Annals of neurology.

[39]  N. Ip,et al.  Trauma‐induced striatal CNTF and BDNF mRNA in hemiparkinsonian rats , 1997, Neuroreport.

[40]  A. Takeda,et al.  Coordinated expression of messenger RNAs for nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the rat hippocampus following transient forebrain ischemia , 1993, Neuroscience.

[41]  Lee Goldman,et al.  Cecil Textbook of Medicine , 1985 .

[42]  G. Yancopoulos,et al.  The neurotrophins and their receptors. , 1993, Trends in cell biology.

[43]  G. Donnan,et al.  Surgical damage stimulates proliferation of dopamine uptake sites in normal mouse brain , 1993, Brain Research.

[44]  Stanley J. Wiegand,et al.  Neurotrophic factors: from molecule to man , 1994, Trends in Neurosciences.

[45]  O. Lindvall,et al.  Increased production of the TrkB protein tyrosine kinase receptor after brain insults , 1993, Neuron.

[46]  E. Oldfield,et al.  Long-term evaluation of hemiparkinsonian monkeys after adrenal autografting or cavitation alone. , 1990, Journal of neurosurgery.

[47]  M. Barbacid,et al.  Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system. , 1990, Development.

[48]  Y. Barde,et al.  Regional distribution of brain‐derived neurotrophic factor mRNA in the adult mouse brain. , 1990, The EMBO journal.

[49]  T. Hökfelt,et al.  Increased levels of trkB mRNA and trkB protein-like immunoreactivity in the injured rat and cat spinal cord. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[50]  M. Barbacid,et al.  Induction of noncatalytic TrkB neurotrophin receptors during axonal sprouting in the adult hippocampus , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[51]  R. Lindsay,et al.  Brain‐Derived Neurotrophic Factor Protects Dopamine Neurons Against 6‐Hydroxydopamine and N‐Methyl‐4‐Phenylpyridinium Ion Toxicity: Involvement of the Glutathione System , 1992, Journal of neurochemistry.

[52]  O. Lindvall,et al.  Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. , 1992, Proceedings of the National Academy of Sciences of the United States of America.