Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons
1-methyl-4-phenyl-1; 2; 3; 6-tetrahydropyridine mptp; adult brain; Biotechnology & Applied Microbiology; central-nervous-system; dopaminergic; gene-transfer; growth factor; juvenile neocortex; mouse-brain; neurotoxicity; parkinsons-disease; replacement
We investigated the hypothesis that neural stem cells (NSCs) possess an intrinsic capacity to "rescue" dysfunctional neurons in the brains of aged mice. The study focused on a neuronal cell type with stereotypical projections that is commonly compromised in the aged brain-the dopaminergic (DA) neuron. Unilateral implantation of murine NSCs into the midbrains of aged mice, in which the presence of stably impaired but nonapoptotic DA neurons was increased by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was associated with bilateral reconstitution of the mesostriatal system. Functional assays paralleled the spatiotemporal recovery of tyrosine hydroxylase (TH) and dopamine transporter (DAT) activity, which, in turn, mirrored the spatiotemporal distribution of donor-derived cells. Although spontaneous conversion of donor NSCs to TH+ cells contributed to nigral reconstitution in DA-depleted areas, the majority of DA neurons in the mesostriatal system were "rescued" host cells. Undifferentiated donor progenitors spontaneously expressing neuroprotective substances provided a plausible molecular basis for this finding. These observations suggest that host structures may benefit not only from NSC-derived replacement of lost neurons but also from the "chaperone" effect of some NSC-derived progeny.
Ourednik J; Ourednik V; Lynch W P; Schachner M; Snyder E Y
Nature Biotechnology
2002
2002-11
Journal Article
<a href="http://doi.org/10.1038/nbt750" target="_blank" rel="noreferrer noopener">10.1038/nbt750</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>