TY - JOUR
T1 - Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA
AU - Sciamanna, Giuseppe
AU - Hollis, Robert
AU - Ball, Chelsea
AU - Martella, Giuseppina
AU - Tassone, Annalisa
AU - Marshall, Andrea
AU - Parsons, Dee
AU - Li, Xinru
AU - Yokoi, Fumiaki
AU - Zhang, Lin
AU - Li, Yuqing
AU - Pisani, Antonio
AU - Standaert, David G.
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
KW - Acetylcholine
KW - Cholinergic interneuron
KW - Conditional knock-out
KW - Dystonia
KW - DYT1
KW - Electrophysiology
KW - TorsinA
UR - http://www.scopus.com/inward/record.url?scp=84863422091&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863422091&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2012.04.015
DO - 10.1016/j.nbd.2012.04.015
M3 - Article
C2 - 22579992
AN - SCOPUS:84863422091
VL - 47
SP - 416
EP - 427
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 3
ER -