Alteration of the cholinergic system and motor deficits in cholinergic neuron-specific Dyt1 knockout mice.
Liu Yuning,Xing Hong,Sheng Wanhui,Singh Kyle N,Korkmaz Alexandra G,Comeau Caroline,Anika Maisha,Ernst Alexis,Yokoi Fumiaki,Vaillancourt David E,Frazier Charles J,Li Yuqing
Neurobiology of disease
Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, repetitive movement, and sometimes abnormal postures. DYT1 dystonia is one of the most common genetic dystonias, and most patients carry heterozygous DYT1 ∆GAG mutations causing a loss of a glutamic acid of the protein torsinA. Patients can be treated with anticholinergics, such as trihexyphenidyl, suggesting an abnormal cholinergic state. Early work on the cell-autonomous effects of Dyt1 deletion with ChI-specific Dyt1 conditional knockout mice (Dyt1 Ch1KO) revealed abnormal electrophysiological responses of striatal ChIs to muscarine and quinpirole, motor deficits, and no changes in the number or size of the ChIs. However, the Chat-cre line that was used to derive Dyt1 Ch1KO mice contained a neomycin cassette and was reported to have ectopic cre-mediated recombination. In this study, we generated a Dyt1 Ch2KO mouse line by removing the neomycin cassette in Dyt1 Ch1KO mice. The Dyt1 Ch2KO mice showed abnormal paw clenching behavior, motor coordination and balance deficits, impaired motor learning, reduced striatal choline acetyltransferase protein level, and a reduced number of striatal ChIs. Furthermore, the mutant striatal ChIs had a normal muscarinic inhibitory function, impaired quinpirole-mediated inhibition, and altered current density. Our findings demonstrate a cell-autonomous effect of Dyt1 deletion on the striatal ChIs and a critical role for the striatal ChIs and corticostriatal pathway in the pathogenesis of DYT1 dystonia.
Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of TOR1A dystonia.
Downs Anthony M,Fan Xueliang,Kadakia Radhika F,Donsante Yuping,Jinnah H A,Hess Ellen J
Neurobiology of disease
TOR1A-associated dystonia, otherwise known as DYT1 dystonia, is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca signaling, D2 dopamine autoreceptor function and GABA receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.
The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network.
Knorr Susanne,Rauschenberger Lisa,Pasos Uri Ramirez,Friedrich Maximilian U,Peach Robert L,Grundmann-Hauser Kathrin,Ott Thomas,O'Leary Aet,Reif Andreas,Tovote Philip,Volkmann Jens,Ip Chi Wang
Neurobiology of disease
TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30-40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin, nNOS, calretinin, ChAT interneurons and Nissl cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.