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Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice
LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633343/ https://www.ncbi.nlm.nih.gov/pubmed/28930069 http://dx.doi.org/10.7554/eLife.28377 |
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author | Volta, Mattia Beccano-Kelly, Dayne A Paschall, Sarah A Cataldi, Stefano MacIsaac, Sarah E Kuhlmann, Naila Kadgien, Chelsie A Tatarnikov, Igor Fox, Jesse Khinda, Jaskaran Mitchell, Emma Bergeron, Sabrina Melrose, Heather Farrer, Matthew J Milnerwood, Austen J |
author_facet | Volta, Mattia Beccano-Kelly, Dayne A Paschall, Sarah A Cataldi, Stefano MacIsaac, Sarah E Kuhlmann, Naila Kadgien, Chelsie A Tatarnikov, Igor Fox, Jesse Khinda, Jaskaran Mitchell, Emma Bergeron, Sabrina Melrose, Heather Farrer, Matthew J Milnerwood, Austen J |
author_sort | Volta, Mattia |
collection | PubMed |
description | LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD. |
format | Online Article Text |
id | pubmed-5633343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-56333432017-10-11 Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice Volta, Mattia Beccano-Kelly, Dayne A Paschall, Sarah A Cataldi, Stefano MacIsaac, Sarah E Kuhlmann, Naila Kadgien, Chelsie A Tatarnikov, Igor Fox, Jesse Khinda, Jaskaran Mitchell, Emma Bergeron, Sabrina Melrose, Heather Farrer, Matthew J Milnerwood, Austen J eLife Chromosomes and Gene Expression LRRK2 mutations produce end-stage Parkinson’s disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD. eLife Sciences Publications, Ltd 2017-09-20 /pmc/articles/PMC5633343/ /pubmed/28930069 http://dx.doi.org/10.7554/eLife.28377 Text en © 2017, Volta et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Chromosomes and Gene Expression Volta, Mattia Beccano-Kelly, Dayne A Paschall, Sarah A Cataldi, Stefano MacIsaac, Sarah E Kuhlmann, Naila Kadgien, Chelsie A Tatarnikov, Igor Fox, Jesse Khinda, Jaskaran Mitchell, Emma Bergeron, Sabrina Melrose, Heather Farrer, Matthew J Milnerwood, Austen J Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice |
title | Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice |
title_full | Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice |
title_fullStr | Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice |
title_full_unstemmed | Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice |
title_short | Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice |
title_sort | initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in lrrk2 g2019s knock-in mice |
topic | Chromosomes and Gene Expression |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633343/ https://www.ncbi.nlm.nih.gov/pubmed/28930069 http://dx.doi.org/10.7554/eLife.28377 |
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