Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons.
Författare
Summary, in English
We used in vivo amperometry to monitor changes in synaptic dopamine (DA) release in the striatum induced by overexpression of human wild-type α-synuclein in nigral DA neurons, induced by injection of an adeno-associated virus type 6 (AAV6)-α-synuclein vector unilaterally into the substantia nigra in adult rats. Impairments in DA release evolved in parallel with the development of degenerative changes in the nigrostriatal axons and terminals. The earliest change, seen 10 d after vector injection, was a marked, ≈50%, reduction in DA reuptake, consistent with an early dysfunction of the DA transporter that developed before any overt signs of axonal damage. At 3 wk, when the first signs of axonal damage were observed, the amount of DA released after a KCl pulse was reduced by 70-80%, and peak DA concentration was delayed, indicating an impaired release mechanism. At later time points, 8-16 wk, overall striatal innervation density was reduced by 60-80% and accompanied by abundant signs of axonal damage in the form of α-synuclein aggregates, axonal swellings, and dystrophic axonal profiles. At this stage DA release and reuptake were profoundly reduced, by 80-90%. The early changes in synaptic DA release induced by overexpression of human α-synuclein support the idea that early predegenerative changes in the handling of DA may initiate, and drive, a progressive degenerative process that hits the axons and terminals first. Synaptic dysfunction and axonopathy would thus be the hallmark of presymptomatic and early-stage Parkinson disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.
Publiceringsår
2012
Språk
Engelska
Sidor
3213-3219
Publikation/Tidskrift/Serie
Proceedings of the National Academy of Sciences
Volym
109
Issue
9
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
National Academy of Sciences
Ämne
- Neurosciences
Nyckelord
- synaptic transmission
- neurodegeneration
Status
Published
Forskningsgrupp
- Neurobiology
ISBN/ISSN/Övrigt
- ISSN: 1091-6490