Reduction In The Number Of Spinal Motor-neurons In Neurotrophin-3-deficient Mice
bdnf; cell-death; cord; expression; fusimotor neurons; motoneurons; motor neurons; muscle spindles; nerve; Neurosciences & Neurology; neurotrophic factor; neurotrophins; proprioception; rat muscle-spindles; size; survival
The effects of a deficiency of neurotrophin-3 on spinal motor neurons were assessed by determining the number of myelinated nerve fibers in lumbar ventral spinal roots of mice with a deletion in the neurotrophin-3 gene. Few or no small-caliber (fusimotor) nerve fibers were present in the L4 ventral root of homozygous mutant mice lacking both copies of the neurotrophin-3 gene, and approximately one-half of the normal complement of the fibers was present in heterozygous mice having one copy of the neurotrophin-3 gene relative to wild type mice at two weeks of age. Numbers of fusimotor nerve fibers paralleled numbers of muscle spindles, the target organs of fusimotor innervation, in hindlimb muscles. Muscle spindles and intrafusal fibers were absent in the soleus muscles of homozygous mutants, and were reduced by approximately 50% in heterozygous relative to wild type mice in accord with previous reports. Neurotrophin-3 might be generated by the intrafusal fibers and may provide a target-derived neurotrophic support for developing fusimotor neurons because in the absence of muscle spindles the neurons did not differentiate and/or survive. In contrast, a great majority of skeletomotor neurons that innervate extrafusal muscle fibers differentiated normally in the absence of neurotrophin-3. This study, analysed in conjunction with our previously reported data, suggests that neurotrophin-3 acts in a coordinated fashion to support, either directly or indirectly, the development of each of the three classes of cells-Ia and Ib sensory neurons, fusimotor neurons, and intrafusal muscle fibers-that comprise the limb proprioceptive system.
Kucera J; Ernfors P; Walro J; Jaenisch R
Neuroscience
1995
1995-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/0306-4522(95)00221-4" target="_blank" rel="noreferrer noopener">10.1016/0306-4522(95)00221-4</a>
Methamphetamine-induced Loss Of Striatal Dopamine Innervation In Bdnf Heterozygote Mice Does Not Further Reduce D-3 Receptor Concentrations
1-methyl-4-phenyl-1; 2; 3; 6-tetrahydropyridine mptp; behavioral; caudate putamen; differential regulation; dopamine; haloperidol treatment; monkey; motor neurons; mutant mice; Neurosciences & Neurology; neurotrophic factor; nucleus accumbens; parkinsons-disease; parkinsons-disease; sensitization; Striatum; substantia-nigra; transporter; tyrosine hydroxylase
Depletion of dopamine (DA) reduces D, receptor number, but D-3 receptor expression is also regulated by brain-derived neurotrophic factor (BDNF). We took advantage of transgenic heterozygous BDNF mutant mice (+/-) to determine if reduced BDNF and loss of DA fibers produced by methamphetamine were additive in their impact on D-3 receptor number. We assessed selective markers of the dopaminergic system including caudate-putamen DA concentrations and quantitative autoradiographic measurement of tyrosine hydroxylase (TH) levels, DA transporter (DAT), and DA D-3 receptor binding between vehicle and methamphetamine-treated BDNF +/- and their wildtype (WT) littermate control mice. Caudate-putamen DA concentrations, TH and DAT levels were significantly reduced following methamphetamine treatment in both WT and BDNF +/- mice. The extent of methamphetamine-induced reduction in TH and DAT was greater for the WT than BDNF +/- mice and DAT levels were also decreased to a greater extent in nucleus accumbens of WT as compared to BDNF +/- mice. Lower D-3 receptor existed in caudate-putamen and nucleus accumbens in BDNF +/- mice and these differences were not affected by methamphetamine treatment. Taken together, these results not only substantiate the importance of BDNF in controlling D-3 receptor expression, but also indicate that a methamphetamine-induced depletion of DA fibers fails to produce an additive effect with lowered BDNF for control of D-3 receptor expression. In addition, the reduction of D-3 receptor expression is associated with a decreased neurotoxic response to methamphetamine in BDNF +/- mice. (C) 2004 Wiley-Liss, Inc.
Joyce J N; Renish L; Osredkar T; Walro J M; Kucera J; Dluzen D E
Synapse
2004
2004-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/syn.10309" target="_blank" rel="noreferrer noopener">10.1002/syn.10309</a>
Inhibition Of Phosphorylation Of Trkb And Trkc And Their Signal Transduction By Alpha(2)-macroglobulin
alpha(2)-macroglobulin; alpha(2)-macroglobulin; alpha(2)-macroglobulin; Alzheimer's disease; Biochemistry & Molecular Biology; cerebrospinal-fluid; dopaminergic-neurons; mitogen-activated protein kinases; nerve growth-factor; neurite outgrowth; Neurodegenerative diseases; Neurosciences & Neurology; neurotrophic factor; neurotrophins; phospholipase C-gamma 1; rat caudate-putamen; signal-transduction; tyrosine protein-kinase
Monoamine-activated alpha(2)-macroglobulin (alpha(2)M) was shown to reduce the dopamine concentration in corpus striatum of adult rat brains and inhibit other neuronal functions in vivo and in vitro. As brain-derived neurotrophic factor, neurotrophin-4, and neurotrophin-3 are important neurotrophic factors for dopaminergic neurons, the effect of monoamine-activated alpha(2)M on signal transduction by trkB and trkC was investigated. The results show that monoamine-activated alpha(2)M binds to trkB and inhibits brain-derived neurotrophic factor/neurotrophin-4-promoted autophosphorylation of trkB in a dose-dependent manner in both trkB-expressing NIH3T3 (NIH3T3-trkB) and human neuroblastoma SH-SY5Y cells. Monoamine-activated alpha(2)M also blocks tyrosine phosphorylation of phospholipase C-gamma 1 and extracellular signal-regulated protein kinase(ERK)-1,which are key intracellular proteins involved in trkB signal transduction. Similarly, monoamine-activated alpha(2)M inhibits tyrosine phosphorylation of neurotrophin-3-induced trkC and its signal transduction in a dose-dependent manner in NIH3T3 cells expressing trkC (NIH3T3-trkC). In contrast to monoamine-activated alpha(2)M, normal alpha(2)M has little or no significant inhibitory effect on the phosphorylation of trkB and trkC. In addition, the retinoic acid-promoted tyrosine phosphorylation of phospholipase C-gamma 1, ERK-1, and/or ERK-2 in SH-SY5Y cells was unaffected by monoamine-activated alpha(2)M; this suggests that the inhibitory effect of activated alpha(2)M on the neurotrophin-stimulated phosphorylation of intracellular signalling proteins may be specific. Taken together, the data indicate that activated alpha(2)M is a pan-trk inhibitor, which by virtue of its binding to trk receptors may block trk-mediated signal transduction in dopaminergic neurons and lead to reduction of dopamine concentration in corpus striatum.
Hu Y Q; Koo P H
Journal of Neurochemistry
1998
1998-07
Journal Article or Conference Abstract Publication
n/a
Developmental And Genetic Influences Upon Gender Differences In Methamphetamine-induced Nigrostriatal Dopaminergic Neurotoxicity
bdnf mutant mice; brain; brain-derived neurotrophic factor (BDNF); differentiation; dopamine; estrogen; female mice; gonadal-hormones; messenger-rna; mptp-induced neurotoxicity; neurodegeneration; neuroprotection; neurotrophic factor; parkinsons-disease; sexual; sexual differences; testosterone; ventral mesencephalon
Dluzen D E; McDermott J L
Current Status of Drug Dependence / Abuse Studies: Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity
2004
2004
Book Chapter
n/a
BDNF protects against stress-induced impairments in spatial learning and memory and UP
adult-rat; brain; central-nervous-system; hippocampal pyramidal neurons; hippocampus; in-vivo; knockout mice; long-term potentiation; neuroprotection; Neurosciences & Neurology; neurotrophic factor; neurotrophins; rat; synaptic plasticity; synaptic transmission
The present study investigated whether infusion of brain-derived neurotrophic factor (BDNF) could ameliorate stress-induced impairments in spatial learning and memory as well as hippocampal long-term potentiation (LTP) of rats. Chronic immobilization stress (2 h/day X 7 days) significantly impaired spatial performance in the Morris water maze, elevated plasma corticosterone, and attenuated LTP in hippocampal slices from these animals as compared with normal control subjects. BDNF was infused into the left hippocampus (0.5 mu l/h) for 14 days, beginning 7 days before the stress exposure. The BDNF group was protected from the deleterious effects of stress and performed at a level indistinguishable from normal control animals despite the presence of elevated corticosterone. BDNF alone and sham infusions had no effect on performance or LTP. These results demonstrate that spatial learning and memory, and LTP, a candidate neural substrate of learning and memory, are compromised during chronic stress, and may be protected by BDNF administration. (c) 2004 Wiley-Liss, Inc.
Radecki D T; Brown L M; Martinez J; Teyler T J
Hippocampus
2005
2005
Journal Article
<a href="http://doi.org/10.1002/hipo.20048" target="_blank" rel="noreferrer noopener">10.1002/hipo.20048</a>