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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
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.
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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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