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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/28377 |
| _version_ | 1811199807892488192 |
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| author | Mattia Volta Dayne A Beccano-Kelly Sarah A Paschall Stefano Cataldi Sarah E MacIsaac Naila Kuhlmann Chelsie A Kadgien Igor Tatarnikov Jesse Fox Jaskaran Khinda Emma Mitchell Sabrina Bergeron Heather Melrose Matthew J Farrer Austen J Milnerwood |
| author_facet | Mattia Volta Dayne A Beccano-Kelly Sarah A Paschall Stefano Cataldi Sarah E MacIsaac Naila Kuhlmann Chelsie A Kadgien Igor Tatarnikov Jesse Fox Jaskaran Khinda Emma Mitchell Sabrina Bergeron Heather Melrose Matthew J Farrer Austen J Milnerwood |
| author_sort | Mattia Volta |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T01:54:45Z |
| format | Article |
| id | doaj.art-5f108c2a552e4725bf106dfb1e5ec4fe |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:54:45Z |
| publishDate | 2017-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5f108c2a552e4725bf106dfb1e5ec4fe2022-12-22T03:52:50ZengeLife Sciences Publications LtdeLife2050-084X2017-09-01610.7554/eLife.28377Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in miceMattia Volta0https://orcid.org/0000-0002-0300-6796Dayne A Beccano-Kelly1https://orcid.org/0000-0003-3592-8354Sarah A Paschall2https://orcid.org/0000-0003-1440-4412Stefano Cataldi3https://orcid.org/0000-0001-7708-4124Sarah E MacIsaac4Naila Kuhlmann5Chelsie A Kadgien6Igor Tatarnikov7Jesse Fox8Jaskaran Khinda9Emma Mitchell10Sabrina Bergeron11Heather Melrose12Matthew J Farrer13Austen J Milnerwood14https://orcid.org/0000-0002-0056-1778Centre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Graduate Program in Neurosciences, University of British Columbia, Vancouver, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaMayo Clinic, Jacksonville, United StatesCentre for Applied Neurogenetics, University of British Columbia, Vancouver, CanadaCentre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada; Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, CanadaLRRK2 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.https://elifesciences.org/articles/28377synapseParkinson's diseaseParkinsonismLRRK2glutamatedopamine |
| spellingShingle | Mattia Volta Dayne A Beccano-Kelly Sarah A Paschall Stefano Cataldi Sarah E MacIsaac Naila Kuhlmann Chelsie A Kadgien Igor Tatarnikov Jesse Fox Jaskaran Khinda Emma Mitchell Sabrina Bergeron Heather Melrose Matthew J Farrer Austen J Milnerwood Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice eLife synapse Parkinson's disease Parkinsonism LRRK2 glutamate dopamine |
| 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 | synapse Parkinson's disease Parkinsonism LRRK2 glutamate dopamine |
| url | https://elifesciences.org/articles/28377 |
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