Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains.
KEY POINTS: The voltage-gated Ca(2+) channels (VGCCs) that catalyse striatal dopamine transmission are critical to dopamine function and might prime subpopulations of neurons for parkinsonian degeneration. However, the VGCCs that operate on mesostriatal axons are incompletely defined; previous studi...
| Үндсэн зохиолчид: | , , , |
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| Формат: | Journal article |
| Хэл сонгох: | English |
| Хэвлэсэн: |
Wiley
2015
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| _version_ | 1826260010964877312 |
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| author | Brimblecombe, K Gracie, C Platt, N Cragg, S |
| author_facet | Brimblecombe, K Gracie, C Platt, N Cragg, S |
| author_sort | Brimblecombe, K |
| collection | OXFORD |
| description | KEY POINTS: The voltage-gated Ca(2+) channels (VGCCs) that catalyse striatal dopamine transmission are critical to dopamine function and might prime subpopulations of neurons for parkinsonian degeneration. However, the VGCCs that operate on mesostriatal axons are incompletely defined; previous studies encompassed channels on striatal cholinergic interneurons that strongly influence dopamine transmission. We define that multiple types of axonal VGCCs operate that extend beyond classic presynaptic N/P/Q channels to include T- and L-types. We reveal differences in VGCC function between mouse axon types that in humans are vulnerable versus resistant to Parkinson's disease. We show for the first time that this is underpinned by different sensitivity of dopamine transmission to extracellular Ca(2+) and by different spatiotemporal intracellular Ca(2+) microdomains. These data define key principles of how Ca(2+) and VGCCs govern dopamine transmission in the healthy brain and reveal differences between neuron types that might contribute to vulnerability in disease. ABSTRACT: The axonal voltage-gated Ca(2+) channels (VGCCs) that catalyse dopamine (DA) transmission are incompletely defined. Yet, they are critical to DA function and might prime subpopulations of DA neurons for parkinsonian degeneration. Previous studies of VGCCs will have encompassed those on striatal cholinergic interneurons, which strongly influence DA transmission. We identify which VGCCs on DA axons govern DA transmission, we determine their dynamic properties and reveal an underlying basis for differences between the caudate putamen (CPu) and nucleus accumbens (NAc). We detected DA release evoked electrically during nicotinic receptor blockade or optogenetically by light activation of channel rhodopsin-expressing DA axons in mouse striatal slices. Subtype-specific VGCC blockers indicated that N-, Q-, T- and L-VGCCs govern DA release in CPu, but in NAc, T and L-channels are relatively silent. The roles of the most dominant channels were inversely frequency-dependent, due to low-pass filtering of DA release by Ca(2+)-dependent relationships between initial release probability and short-term plasticity. Ca(2+) concentration-response curves revealed that differences between CPu and NAc were due to greater underlying Ca(2+) sensitivity of DA transmission from CPu axons. Functions for 'silent' L- and T-channels in NAc could be unmasked by elevating extracellular [Ca(2+)]. Furthermore, we identified a greater coupling between BAPTA-sensitive, fast Ca(2+) transients and DA transmission in CPu axons, and evidence for endogenous fast buffering of Ca(2+) in NAc. These data reveal that a range of VGCCs operate dynamically on DA axons, depending on local driving forces. Furthermore, they reveal dramatic differences in Ca(2+) handling between axonal subpopulations that show different vulnerability to parkinsonian degeneration. |
| first_indexed | 2024-03-06T18:58:51Z |
| format | Journal article |
| id | oxford-uuid:12d4026d-2268-4219-b7b2-cb68880b2d96 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:58:51Z |
| publishDate | 2015 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:12d4026d-2268-4219-b7b2-cb68880b2d962022-03-26T10:10:11ZGating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:12d4026d-2268-4219-b7b2-cb68880b2d96EnglishSymplectic Elements at OxfordWiley2015Brimblecombe, KGracie, CPlatt, NCragg, SKEY POINTS: The voltage-gated Ca(2+) channels (VGCCs) that catalyse striatal dopamine transmission are critical to dopamine function and might prime subpopulations of neurons for parkinsonian degeneration. However, the VGCCs that operate on mesostriatal axons are incompletely defined; previous studies encompassed channels on striatal cholinergic interneurons that strongly influence dopamine transmission. We define that multiple types of axonal VGCCs operate that extend beyond classic presynaptic N/P/Q channels to include T- and L-types. We reveal differences in VGCC function between mouse axon types that in humans are vulnerable versus resistant to Parkinson's disease. We show for the first time that this is underpinned by different sensitivity of dopamine transmission to extracellular Ca(2+) and by different spatiotemporal intracellular Ca(2+) microdomains. These data define key principles of how Ca(2+) and VGCCs govern dopamine transmission in the healthy brain and reveal differences between neuron types that might contribute to vulnerability in disease. ABSTRACT: The axonal voltage-gated Ca(2+) channels (VGCCs) that catalyse dopamine (DA) transmission are incompletely defined. Yet, they are critical to DA function and might prime subpopulations of DA neurons for parkinsonian degeneration. Previous studies of VGCCs will have encompassed those on striatal cholinergic interneurons, which strongly influence DA transmission. We identify which VGCCs on DA axons govern DA transmission, we determine their dynamic properties and reveal an underlying basis for differences between the caudate putamen (CPu) and nucleus accumbens (NAc). We detected DA release evoked electrically during nicotinic receptor blockade or optogenetically by light activation of channel rhodopsin-expressing DA axons in mouse striatal slices. Subtype-specific VGCC blockers indicated that N-, Q-, T- and L-VGCCs govern DA release in CPu, but in NAc, T and L-channels are relatively silent. The roles of the most dominant channels were inversely frequency-dependent, due to low-pass filtering of DA release by Ca(2+)-dependent relationships between initial release probability and short-term plasticity. Ca(2+) concentration-response curves revealed that differences between CPu and NAc were due to greater underlying Ca(2+) sensitivity of DA transmission from CPu axons. Functions for 'silent' L- and T-channels in NAc could be unmasked by elevating extracellular [Ca(2+)]. Furthermore, we identified a greater coupling between BAPTA-sensitive, fast Ca(2+) transients and DA transmission in CPu axons, and evidence for endogenous fast buffering of Ca(2+) in NAc. These data reveal that a range of VGCCs operate dynamically on DA axons, depending on local driving forces. Furthermore, they reveal dramatic differences in Ca(2+) handling between axonal subpopulations that show different vulnerability to parkinsonian degeneration. |
| spellingShingle | Brimblecombe, K Gracie, C Platt, N Cragg, S Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. |
| title | Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. |
| title_full | Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. |
| title_fullStr | Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. |
| title_full_unstemmed | Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. |
| title_short | Gating of dopamine transmission by calcium and axonal N-, Q-, T- and L-type voltage-gated calcium channels differs between striatal domains. |
| title_sort | gating of dopamine transmission by calcium and axonal n q t and l type voltage gated calcium channels differs between striatal domains |
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