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Functional properties and synaptic integration of genetically labelled dopaminergic neurons in intrastriatal grafts.

Toft Sörensen, Andreas LU ; Thompson, Lachlan LU ; Kirik, Deniz LU ; Björklund, Anders LU ; Lindvall, Olle LU and Kokaia, Merab LU (2005) In European Journal of Neuroscience 21(10). p.2793-2799
Abstract
ntrastriatal grafts of fetal ventral mesencephalic tissue, rich in dopaminergic neurons, can reverse symptoms in Parkinson's disease. For development of effective cell replacement therapy, other sources of dopaminergic neurons, e.g. derived from stem cells, are needed. However, the electrophysiological properties grafted cells need to have in order to induce substantial functional recovery are poorly defined. It has not been possible to prospectively identify and record from dopaminergic neurons in fetal transplants. Here we used transgenic mice expressing green fluorescent protein under control of the rat tyrosine hydroxylase promoter for whole-cell patch-clamp recordings of endogenous and grafted dopaminergic neurons. We transplanted... (More)
ntrastriatal grafts of fetal ventral mesencephalic tissue, rich in dopaminergic neurons, can reverse symptoms in Parkinson's disease. For development of effective cell replacement therapy, other sources of dopaminergic neurons, e.g. derived from stem cells, are needed. However, the electrophysiological properties grafted cells need to have in order to induce substantial functional recovery are poorly defined. It has not been possible to prospectively identify and record from dopaminergic neurons in fetal transplants. Here we used transgenic mice expressing green fluorescent protein under control of the rat tyrosine hydroxylase promoter for whole-cell patch-clamp recordings of endogenous and grafted dopaminergic neurons. We transplanted ventral mesencephalic tissue from E12.5 transgenic mice into striatum of neonatal rats with or without lesions of the nigrostriatal dopamine system. The transplanted cells exhibited intrinsic electrophysiological properties typical of substantia nigra dopaminergic neurons, i.e. broad action potentials, inward rectifying currents with characteristic 'sag', and spontaneous action potentials. The grafted dopaminergic neurons also received functional excitatory and inhibitory synaptic inputs from the host brain, as shown by the presence of both spontaneous and stimulation-evoked excitatory and inhibitory postsynaptic currents. Occurrence of spontaneous excitatory and inhibitory currents was lower, and of spontaneous action potentials was higher, in neurons placed in the dopamine-depleted striatum than of those in the intact striatum. Our findings define specific electrophysiological characteristics of transplanted fetal dopaminergic neurons, and we provide the first direct evidence of functional synaptic integration of these neurons into host neural circuitries. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
rats, Parkinson's disease, electrophysiology, dopaminergic neurons, stem cells, transplantation
in
European Journal of Neuroscience
volume
21
issue
10
pages
2793 - 2799
publisher
Wiley-Blackwell
external identifiers
  • wos:000229369700017
  • pmid:15926926
  • scopus:20644464349
ISSN
1460-9568
DOI
10.1111/j.1460-9568.2005.04116.x
language
English
LU publication?
yes
id
226b272b-330f-45fe-968b-397ef2505fcc (old id 140407)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15926926&query_hl=111
date added to LUP
2007-07-17 10:42:03
date last changed
2017-01-15 03:34:06
@article{226b272b-330f-45fe-968b-397ef2505fcc,
  abstract     = {ntrastriatal grafts of fetal ventral mesencephalic tissue, rich in dopaminergic neurons, can reverse symptoms in Parkinson's disease. For development of effective cell replacement therapy, other sources of dopaminergic neurons, e.g. derived from stem cells, are needed. However, the electrophysiological properties grafted cells need to have in order to induce substantial functional recovery are poorly defined. It has not been possible to prospectively identify and record from dopaminergic neurons in fetal transplants. Here we used transgenic mice expressing green fluorescent protein under control of the rat tyrosine hydroxylase promoter for whole-cell patch-clamp recordings of endogenous and grafted dopaminergic neurons. We transplanted ventral mesencephalic tissue from E12.5 transgenic mice into striatum of neonatal rats with or without lesions of the nigrostriatal dopamine system. The transplanted cells exhibited intrinsic electrophysiological properties typical of substantia nigra dopaminergic neurons, i.e. broad action potentials, inward rectifying currents with characteristic 'sag', and spontaneous action potentials. The grafted dopaminergic neurons also received functional excitatory and inhibitory synaptic inputs from the host brain, as shown by the presence of both spontaneous and stimulation-evoked excitatory and inhibitory postsynaptic currents. Occurrence of spontaneous excitatory and inhibitory currents was lower, and of spontaneous action potentials was higher, in neurons placed in the dopamine-depleted striatum than of those in the intact striatum. Our findings define specific electrophysiological characteristics of transplanted fetal dopaminergic neurons, and we provide the first direct evidence of functional synaptic integration of these neurons into host neural circuitries.},
  author       = {Toft Sörensen, Andreas and Thompson, Lachlan and Kirik, Deniz and Björklund, Anders and Lindvall, Olle and Kokaia, Merab},
  issn         = {1460-9568},
  keyword      = {rats,Parkinson's disease,electrophysiology,dopaminergic neurons,stem cells,transplantation},
  language     = {eng},
  number       = {10},
  pages        = {2793--2799},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Neuroscience},
  title        = {Functional properties and synaptic integration of genetically labelled dopaminergic neurons in intrastriatal grafts.},
  url          = {http://dx.doi.org/10.1111/j.1460-9568.2005.04116.x},
  volume       = {21},
  year         = {2005},
}