Increased Cholinergic Response in α-Synuclein Transgenic Mice (h-α-synL62)

Magdalena König, Beata Berlin, Karima Schwab, Silke Frahm, Franz Theuring, Claude M Wischik, Charles R Harrington, Gernot Riedel, Jochen Klein

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Abstract

Pathological accumulation of misfolded α-synuclein (α-syn) in the brain plays a key role in the pathogenesis of Parkinson's disease, leading to neuronal dysfunction and motor disorders. The underlying mechanisms linking α-syn aggregations with neurotransmitter disturbance in Parkinson's brains are not well characterized. In the present study, we investigated transgenic mice expressing an aggregation-prone form of full-length human α-syn (h-α-synL62) linked to a signal sequence. These mice display dopamine depletion and progressive motor deficits. We detected accumulation of α-syn in cholinergic interneurons where they are colocalized with choline acetyltransferase. Using microdialysis, we measured acetylcholine levels in the striatum at baseline and during stimulation in the open field and with scopolamine. While no difference between wild-type and transgenic mice was detected in 3 month old mice, striatal acetylcholine levels at 9 months of age were significantly higher in transgenic mice. Concomitantly, high-affinity choline uptake was also increased while choline acetyltransferase and acetylcholine esterase activities were unchanged. The results suggest a disinhibition of acetylcholine release in α-syn transgenic mice.

Original languageEnglish
Pages (from-to)1915-1922
Number of pages8
JournalACS Chemical Neuroscience
Volume10
Issue number4
Early online date28 Sep 2018
DOIs
Publication statusPublished - 2019

Keywords

  • alpha-synuclein
  • acetylcholine
  • microdialysis
  • cholinergic interneurons
  • scopolamine
  • muscarinic receptors
  • BASAL GANGLIA
  • HIPPOCAMPAL ACETYLCHOLINE-RELEASE
  • MEDIATED MODULATION
  • IN-VIVO
  • DOPAMINE
  • NEURONS
  • Alpha-synuclein
  • ACETYLTRANSFERASE
  • INTERNEURONS
  • BRAIN
  • PARKINSONS-DISEASE

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