Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.
Tønnesen, Jan ; Parish, Clare L ; Toft Sörensen, Andreas LU ; Andersson, Angelica ; Lundberg, Cecilia LU
; Deisseroth, Karl
; Arenas, Ernest
; Lindvall, Olle
LU
and Kokaia, Merab
LU
(2011)
In PLoS ONE
6(3).
- Abstract
- Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D(2) autoreceptors. These properties resembled those recorded from identical cells... (More)
- Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D(2) autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1884080
- author
- Tønnesen, Jan
; Parish, Clare L
; Toft Sörensen, Andreas
LU
; Andersson, Angelica
; Lundberg, Cecilia
LU
; Deisseroth, Karl
; Arenas, Ernest
; Lindvall, Olle
LU
and Kokaia, Merab
LU
- organization
- publishing date
- 2011
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 6
- issue
- 3
- article number
- e17560
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000288025500016
- pmid:21394212
- scopus:79952353120
- pmid:21394212
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0017560
- language
- English
- LU publication?
- yes
- id
- 1d8b9b91-1aff-4a87-949d-3b57a2eb2ca3 (old id 1884080)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/21394212?dopt=Abstract
- date added to LUP
- 2016-04-04 09:08:07
- date last changed
- 2022-05-16 23:00:44
@article{1d8b9b91-1aff-4a87-949d-3b57a2eb2ca3,
abstract = {{Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D(2) autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.}},
author = {{Tønnesen, Jan and Parish, Clare L and Toft Sörensen, Andreas and Andersson, Angelica and Lundberg, Cecilia and Deisseroth, Karl and Arenas, Ernest and Lindvall, Olle and Kokaia, Merab}},
issn = {{1932-6203}},
language = {{eng}},
number = {{3}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.}},
url = {{https://lup.lub.lu.se/search/files/5241028/1890400.pdf}},
doi = {{10.1371/journal.pone.0017560}},
volume = {{6}},
year = {{2011}},
}