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Featured ArticleResearch Articles, Development/Plasticity/Repair

Understanding the Influence of Target Acquisition on Survival, Integration, and Phenotypic Maturation of Dopamine Neurons within Stem Cell-Derived Neural Grafts in a Parkinson's Disease Model

Niamh Moriarty, Jessica A. Kauhausen, Chiara Pavan, Cameron P.J. Hunt, Isabelle R. de Luzy, Vanessa Penna, Charlotte M. Ermine, Lachlan H. Thompson and Clare L. Parish
Journal of Neuroscience 22 June 2022, 42 (25) 4995-5006; DOI: https://doi.org/10.1523/JNEUROSCI.2431-21.2022
Niamh Moriarty
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Jessica A. Kauhausen
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Chiara Pavan
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Cameron P.J. Hunt
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Isabelle R. de Luzy
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Vanessa Penna
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Charlotte M. Ermine
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Lachlan H. Thompson
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Clare L. Parish
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
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Abstract

Midbrain dopaminergic (DA) neurons include many subtypes characterized by their location, connectivity and function. Surprisingly, mechanisms underpinning the specification of A9 neurons [responsible for motor function, including within ventral midbrain (VM) grafts for treating Parkinson's disease (PD)] over adjacent A10, remains largely speculated. We assessed the impact of synaptic targeting on survival, integration, and phenotype acquisition of dopaminergic neurons within VM grafts generated from fetal tissue or human pluripotent stem cells (PSCs). VM progenitors were grafted into female mice with 6OHDA-lesions of host midbrain dopamine neurons, with some animals also receiving intrastriatal quinolinic acid (QA) injections to ablate medium spiny neurons (MSN), the A9 neuron primary target. While loss of MSNs variably affected graft survival, it significantly reduced striatal yet increased cortical innervation. Consequently, grafts showed reduced A9 and increased A10 specification, with more DA neurons failing to mature into either subtype. These findings highlight the importance of target acquisition on DA subtype specification during development and repair.

SIGNIFICANCE STATEMENT Parish and colleagues highlight, in a rodent model of Parkinson's disease (PD), the importance of synaptic target acquisition in the survival, integration and phenotypic specification of grafted dopamine neurons derived from fetal tissue and human stem cells. Ablation of host striatal neurons resulted in reduced dopamine neuron survival within grafts, re-routing of dopamine fibers from striatal to alternate cortical targets and a consequential reduced specification of A9 dopamine neurons (the subpopulation critical for restoration of motor function) and increase in A10 DA neurons.

  • dopamine
  • human pluripotent stem cells
  • Parkinson's disease
  • synaptic plasticity
  • target acquisition
  • transplantation

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The Journal of Neuroscience: 42 (25)
Journal of Neuroscience
Vol. 42, Issue 25
22 Jun 2022
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Understanding the Influence of Target Acquisition on Survival, Integration, and Phenotypic Maturation of Dopamine Neurons within Stem Cell-Derived Neural Grafts in a Parkinson's Disease Model
Niamh Moriarty, Jessica A. Kauhausen, Chiara Pavan, Cameron P.J. Hunt, Isabelle R. de Luzy, Vanessa Penna, Charlotte M. Ermine, Lachlan H. Thompson, Clare L. Parish
Journal of Neuroscience 22 June 2022, 42 (25) 4995-5006; DOI: 10.1523/JNEUROSCI.2431-21.2022

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Understanding the Influence of Target Acquisition on Survival, Integration, and Phenotypic Maturation of Dopamine Neurons within Stem Cell-Derived Neural Grafts in a Parkinson's Disease Model
Niamh Moriarty, Jessica A. Kauhausen, Chiara Pavan, Cameron P.J. Hunt, Isabelle R. de Luzy, Vanessa Penna, Charlotte M. Ermine, Lachlan H. Thompson, Clare L. Parish
Journal of Neuroscience 22 June 2022, 42 (25) 4995-5006; DOI: 10.1523/JNEUROSCI.2431-21.2022
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Keywords

  • dopamine
  • human pluripotent stem cells
  • Parkinson's disease
  • synaptic plasticity
  • target acquisition
  • transplantation

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