title: Glycogen synthase kinase-3 reduces acetylcholine level in striatum via disturbing cellular distribution of choline acetyltransferase in cholinergic interneurons in rats.
abstract: Cholinergic interneurons, which provide the main source of acetylcholine (ACh) in the striatum, control the striatal local circuits and deeply involve in the pathogenesis of neurodegenerative diseases. Glycogen synthase kinase-3 (GSK-3) is a crucial kinase with diverse fundamental functions and accepted that deregulation of GSK-3 activity also plays important roles in diverse neurodegenerative diseases. However, up to now, there is no direct proof indicating whether GSK-3 activation is responsible for cholinergic dysfunction. In the present study, with combined intracerebroventricular injection of Wortmannin and GF-109203X, we activated GSK-3 and demonstrated the increased phosphorylation level of microtubule-associated protein tau and neurofilaments (NFs) in the rat striatum. The activated GSK-3 consequently decreased ACh level in the striatum as a result of the reduction of choline acetyltransferase (ChAT) activity. The alteration of ChAT activity was due to impaired ChAT distribution rather than its expression. Furthermore, we proved that cellular ChAT distribution was dependent on low phosphorylation level of NFs. Nevertheless, the cholinergic dysfunction in the striatum failed to induce significant neuronal number reduction. In summary, our data demonstrates the link between GSK-3 activation and cholinergic dysfunction in the striatum and provided beneficial evidence for the pathogenesis study of relevant neurodegenerative diseases.
authors.affiliation: Department of Neurobiology and Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.forename: C-B
authors.initials: CB
authors.lastname: Chu
authors.forename: J-F
authors.initials: JF
authors.lastname: Li
authors.forename: Y-T
authors.initials: YT
authors.lastname: Yang
authors.forename: S-Q
authors.initials: SQ
authors.lastname: Niu
authors.forename: W
authors.initials: W
authors.lastname: Qin
authors.forename: Y-G
authors.initials: YG
authors.lastname: Hao
authors.forename: Q
authors.initials: Q
authors.lastname: Dong
authors.forename: R
authors.initials: R
authors.lastname: Guan
authors.forename: W-L
authors.initials: WL
authors.lastname: Hu
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002795:Choline O-Acetyltransferase; D038362:Glycogen Synthase Kinase 3; D000109:Acetylcholine
keywords: ACh; AChE; AD; Alzheimer’s disease; ChAT; EGTA; GF-109203X; GFX; GSK-3; HD; HPLC; High-performance liquid chromatography; Huntington’s disease; NFs; PD; Parkinson’s disease; SMI31; SMI33; WT; aCSF; acetylcholine; acetylcholinesterase; artificial cerebrospinal fluid; choline acetyltransferase; ethylene glycol tetraacetic acid; glycogen synthase kinase-3; neurofilaments; nonphosphorylated NFs; pS214; pS396; pS9-GSK-3β; pT231; phosphorylated GSK-3β at Ser 9 epitope; phosphorylated NFs; phosphorylated tau at Ser 214 epitope; phosphorylated tau at Ser 396 epitope; phosphorylated tau at Thr 231 epitope; wortmannin