title: Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA.
abstract: DYT1 dystonia, a common and severe primary dystonia, is caused by a 3-bp deletion in TOR1A which encodes torsinA, a protein found in the endoplasmic reticulum. Several cellular functions are altered by the mutant protein, but at a systems level the link between these and the symptoms of the disease is unclear. The most effective known therapy for DYT1 dystonia is the use of anticholinergic drugs. Previous studies have revealed that in mice, transgenic expression of human mutant torsinA under a non-selective promoter leads to abnormal function of striatal cholinergic neurons. To investigate what pathological role torsinA plays in cholinergic neurons, we created a mouse model in which the Dyt1 gene, the mouse homolog of TOR1A, is selectively deleted in cholinergic neurons (ChKO animals). These animals do not have overt dystonia, but do have subtle motor abnormalities. There is no change in the number or size of striatal cholinergic cells or striatal acetylcholine content, uptake, synthesis, or release in ChKO mice. There are, however, striking functional abnormalities of striatal cholinergic cells, with paradoxical excitation in response to D2 receptor activation and loss of muscarinic M2/M4 receptor inhibitory function. These effects are specific for cholinergic interneurons, as recordings from nigral dopaminergic neurons revealed normal responses. Amphetamine stimulated dopamine release was also unaltered. These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata and Fondazione Santa Lucia, I.R.C.C.S., Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciamanna
authors.forename: Robert
authors.initials: R
authors.lastname: Hollis
authors.forename: Chelsea
authors.initials: C
authors.lastname: Ball
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Martella
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tassone
authors.forename: Andrea
authors.initials: A
authors.lastname: Marshall
authors.forename: Dee
authors.initials: D
authors.lastname: Parsons
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokoi
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Li
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology; D015259:Dopamine Agents / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D061346:Laser Capture Microdissection; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D018408:Patch-Clamp Techniques; D011189:Potassium Chloride / Q000494:pharmacology; D011506:Proteins / Q000235:genetics; D019257:Quinpirole / Q000494:pharmacology; D022661:RNA, Untranslated; D013997:Time Factors; D014316:Tritium / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D018491:Dopamine Agonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D058786:GABA-B Receptor Agonists; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D018832:Molecular Chaperones; D018721:Muscarinic Agonists; D011506:Proteins; D022661:RNA, Untranslated; C108175:TOR1A protein, human; D014316:Tritium; D019257:Quinpirole; D008734:Methoxyhydroxyphenylglycol; D011189:Potassium Chloride; D009116:Muscarine; D000661:Amphetamine; D002795:Choline O-Acetyltransferase; D001616:beta-Galactosidase; D001418:Baclofen; D000109:Acetylcholine; C010117:3,4-dihydroxyphenylglycol