Multiple lines of evidence implicate striatal cholinergic dysfunction in dystonia pathophysiology (Pappas et al., 2015; Albin et al., 2003; Eskow Jaunarajs et al., 2015; Pappas et al., 2014). The symptoms of DYT1 dystonia, caused by a loss of function mutation in the gene encoding torsinA (Ozelius et al., 1997), are reduced by antimuscarinic treatments (e.g., trihexyphenidyl)(Burke et al., 1986). Antimuscarinic agents also reduce motor (Pappas et al., 2015) and electrophysiological (Maltese et al., 2014) abnormalities in DYT1 mouse models. Striatal cholinergic dysfunction is a common feature of multiple DYT1 animal models (Pappas et al., 2015; Martella et al., 2009; Pisani et al., 2006; Sciamanna et al., 2012a; Sciamanna et al., 2012b), and experimental ablation of striatal cholinergic interneurons (ChI) can lead to abnormal postures (Kaneko et al., 2000).

We demonstrated previously that deletion of torsinA from forebrain GABAergic and cholinergic neurons (using Dlx5/6-cre; ‘Dlx-CKO’) causes highly selective degeneration of dorsal striatal ChI roughly coincident with the juvenile onset of abnormal limb clasping and twisting movements(Pappas et al., 2015). Selective ChI abnormalities are also present in postmortem tissue from DYT1 subjects (Pappas et al., 2015). Abnormal movements in Dlx-CKO mice are reduced by clinically relevant antimuscarinic treatments, strengthening model therapeutic validity and suggesting shared pathophysiology with human dystonia. This work highlights the importance of elucidating the mechanism of selective ChI loss. A critical first step toward this goal is to determine whether the ChI loss observed in Dlx-CKO mice results from a cell autonomous role of torsinA in these cells or, alternatively, whether loss of torsinA from synaptically connected cells is also required. The major aim of these studies was to address this fundamental question.

To determine whether torsinA-related ChI loss is cell autonomous, we generated and characterized cholinergic neuron selective conditional torsinA knockout mice (ChAT-CKO). We find that ChAT-CKO mice phenocopy the selective degeneration of dorsal striatal ChI observed in Dlx-CKO mice (basal forebrain neuron numbers are normal in both models). Assessment of non-forebrain cholinergic populations demonstrates that pedunculopontine and laterodorsal tegmental brainstem cholinergic neurons, and spinal motor neurons also require torsinA for survival or normal function. ChAT-CKO mice exhibit severe motor and postural abnormalities that are distinct from Dlx-CKO mice. These findings are the first to establish a cell autonomous requirement for torsinA in ChI, as well as identifying additional vulnerable cholinergic neuron populations. This in vivo study fundamentally advances and expands understanding of the requirement of torsinA for normal cholinergic system function, opening new directions for the study of mechanisms contributing to selective neuronal dysfunction in dystonia.

To determine if ChI neurodegeneration is a cell autonomous effect of torsinA loss, we conditionally deleted torsinA from cholinergic neurons (Chat-IRES-Cre⁺, Tor1a^Flx/-; ‘ChAT-CKO’ mice; Cre-recombinase expression occurs before birth and is completely selective for cholinergic neurons; Figure 1—figure supplement 1 [Madisen et al., 2010]). Unilateral unbiased stereology of ChAT-immunoreactive neurons in the dorsal striatum from 1 year old mice demonstrates a ~ 34% reduction in the number of dorsal striatal ChI in ChAT-CKO mice compared to control mice (Figure 1A,B). This finding was confirmed in an independent cohort using bilateral unbiased stereology (48% reduction; Figure 1—figure supplement 2A). The number of striatal non-cholinergic neurons was not different from controls (Figure 1—figure supplement 2B,C), demonstrating that there are no secondary cell loss effects of ChI degeneration, and that torsinA loss of function-mediated neurodegeneration is highly specific. These findings establish a cell autonomous torsinA requirement for ChI survival.

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ChI cell loss is strikingly selective in Dlx-CKO mice, occurring primarily in the dorsal aspects of the striatum, with approximately six times greater cell loss in the dorsolateral compared to ventromedial striatum (57% vs 9% cell density reduction in Dlx-CKO mice; [Pappas et al., 2015]). To examine if the cell autonomous ChI degeneration in ChAT-CKO mice follows a similar subregion-selective pattern, we determined the density of ChAT-immunoreactive neurons in each quadrant of the dorsal striatum (as previously [Pappas et al., 2015]). Significant reductions in ChI number were limited to the dorsolateral and dorsomedial segments of the dorsal striatum (72% and 54% cell density reductions in dorsolateral and dorsomedial, vs 12% and −4% in ventrolateral and ventromedial segments; Figure 1C). This topographic pattern of cell loss was present throughout the entire rostro-caudal extent of the striatum (Figure 1C,D, Figure 1—figure supplement 3). The dorsolateral selectivity of ChI neuron loss is highly relevant, as the dorsolateral striatum is a key motor circuit node functionally integrated according to topographic inputs, whereas ventromedial striatal neurons are connected in associative and limbic circuits (Alexander et al., 1986; Haber, 2016; Parent and Hazrati, 1995). In contrast, the basal forebrain contains cholinergic projection neurons subserving cognitive and attentional control (Hasselmo and Sarter, 2011; Ballinger et al., 2016), which do not degenerate in either model (Figure 1E,F). Conditional deletion of torsinA from forebrain cholinergic neurons therefore mimics the region-selective vulnerability observed in Dlx-CKO mice, demonstrating a cell autonomous requirement for torsinA in select cholinergic populations. To determine if differing time courses of torsinA loss (via differing torsinA half lives) contributes to selective vulnerability, we assessed torsinA levels in dorsal vs ventral striatal ChI at P0. Surprisingly, despite uniform prenatal Cre recombinase expression and preferential loss of dorsal ChI, torsinA levels were reduced to a greater extent in ventral ChI (dorsal ChI contained 82% of control torsinA levels, while ventral ChI had ~52% remaining; Figure 1—figure supplement 4). Non-vulnerable basal forebrain cholinergic neurons exhibited 49% of control torsinA immunoreactivity (Figure 1—figure supplement 5). These findings demonstrate that a more rapid loss of torsinA during development does not contribute to the unique vulnerability of dorsal ChI.

TorsinA deletion is restricted to forebrain structures in Dlx-CKO mice. In contrast, ChAT-CKO mice lack torsinA in all cholinergic neurons throughout the neuraxis, enabling us to assess the impact of torsinA loss in additional cholinergic populations. Unbiased stereology of ChAT-immunoreactive neurons in the brainstem demonstrates significantly fewer cholinergic neurons in the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei in 1 year old Chat-CKO mice (Figure 2A–D). The PPN and LDT also contain GABAergic, and glutamatergic neurons (Mena-Segovia, 2016), which significantly outnumber cholinergic neurons (Mena-Segovia et al., 2009; Wang and Morales, 2009). Unbiased stereology of NeuN +neurons in PPN and LDT showed no significant change in the overall number of neurons (Figure 2A,C). Because cholinergic neurons are a minority of cells in the PPN and LDT, it is possible that a significant reduction of this small sub-population cannot be detected when assessed by counting overall NeuN +neuron number. It is also possible that PPN and LDT cholinergic neurons exhibit reduced ChAT expression rather than actual cell loss. Regardless, either possibility demonstrates a cell autonomous role for torsinA for normal function of these cells. These findings also indicate that the loss or dysfunction of brainstem cholinergic neurons does not have deleterious effects on the viability of surrounding neurons. Consistent with this finding, there was no evidence of reactive microgliosis or astrogliosis in the brainstem (Figure 2—figure supplement 1). Quantification of the number of spinal motor neurons (C3-C5; [Kim et al., 2017]) demonstrated significantly fewer motor neurons in ChAT-CKO mice (Figure 2E,F).

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The identification of cholinergic dysfunction or loss in PPN and LDT is notable, as considerable data implicate these cells in motor and postural control. PPN and LDT cholinergic neurons are distributed in a rostrocaudal continuum in the brainstem, forming a coordinated functional unit (Mena-Segovia, 2016; Mena-Segovia and Bolam, 2017). PPN and LDT cholinergic neurons topographically innervate the striatum and striatal-projecting thalamic and midbrain dopamine neurons (Dautan et al., 2014), such that rostral PPN modulates motor-related circuits, LDT innervates limbic circuits, and caudal PPN targets both regions (Mena-Segovia, 2016; Xiao et al., 2016) via both direct and indirect inputs. Consistent with a central role in modulating locomotor activity, optogenetic stimulation of PPN cholinergic neurons alters locomotion speed, while stimulation of adjacent glutamatergic neurons induces locomotion (Xiao et al., 2016; Roseberry et al., 2016; Capelli et al., 2017). Cholinergic PPN lesion alone or in combination with dopaminergic denervation impairs gait and causes postural abnormalities in primates (Grabli et al., 2013; Karachi et al., 2010). In rodents, cholinergic-selective PPN lesion impairs performance on the accelerating rotarod and alters sensorimotor gating (MacLaren et al., 2014a; MacLaren et al., 2014b), while non-specific PPN ablation alters gait (Blanco-Lezcano et al., 2017) and impairs reversal learning (Syed et al., 2016). Human neuroimaging and postmortem studies also provide support for a connection between PPN cholinergic integrity and motor function. PPN cholinergic loss is linked to gait abnormalities in Parkinson disease (Karachi et al., 2010; Bohnen et al., 2009), and brainstem lesions (including PPN loss) can result in complex dystonia (Jankovic and Patel, 1983; LeDoux and Brady, 2003; Loher and Krauss, 2009; Zweig et al., 1988; Mente et al., 2018). Systematic cholinergic brainstem cell counts have not been performed in DYT1 dystonia postmortem samples; most studies have failed to demonstrate neuronal inclusions or overt cell loss in this region (Paudel et al., 2014; Pratt et al., 2016; McNaught et al., 2004).

Motor behavior is severely disrupted in ChAT-CKO mice, but is distinct from the Dlx-CKO phenotype (Figure 3; Table 1). ChAT-CKO pups are initially indistinguishable from littermates, but at approximately 4 weeks of age develop a hunched posture, have unkempt fur, and exhibit reduced responsiveness to handling (Figure 3A, Figure 3—figure supplement 1). Whereas normal mice exhibit a slight dorsal spinal curvature at rest, ChAT-CKO mice exhibit severe kyphosis, including during locomotion (assessed by two observers blind to experimental conditions; Figure 3B; Figure 3—figure supplement 1; Figure 3—video 1) (Guyenet et al., 2010). ChAT-CKO mice also exhibit signs of weakness, including a significantly reduced ability to hang by the forelimbs (Figure 3C), tremulous movements, labored breathing (Figure 3—video 1), and significantly reduced horizontal and vertical movement in the open field (Figure 3D,E, Figure 3—figure supplement 2). Remarkably, performance on the accelerating rotarod during two days of training appears normal (Figure 3F). The normal rotarod behavior differs from models of motor neuron and neuromuscular disease, suggesting that neuromuscular weakness is modest in ChAT-CKO, and less likely to contribute to other behavioral phenotypes (e.g., postural abnormality). The gait of ChAT-CKO mice is also significantly altered (Figure 3G–I). This constellation of behavioral phenotypes is distinct from Dlx-CKO mice (Table 1), in which loss of dorsal striatal ChI is associated with a set of persistent abnormal action-induced motor behaviors, including limb clasping and trunk twisting during tail suspension and open field hyperactivity (Pappas et al., 2015). ChAT-CKO mice did not exhibit fore- or hindlimb clasping during tail suspension, but did exhibit tremulousness and trunk twisting (15 CKO, 19 heterozygous, 22 Cre control, and 19 wild type mice observed; Figure 3—video 2). These results suggest that dorsal striatal ChI neurodegeneration may not, by itself, be sufficient to cause limb clasping during tail suspension. However, the co-occurrence of brainstem and spinal cord neurodegeneration and tremulousness in ChAT-CKO mice could modify a clasping phenotype and therefore limit this strength of this conclusion.

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While no single system or experimental approach can fully model a disease, the extreme postural abnormalities (kyphosis and twisting) in ChAT-CKO mice are reminiscent of Oppenheim’s original description of dystonia (Klein and Fahn, 2013), suggesting that a constellation of cholinergic abnormalities may contribute to such a phenotype. The abnormal gait, tremulous movement, weakness, labored breathing, and appearance of reduced muscle mass in ChAT-CKO mice are consistent with brainstem and spinal cord pathology, yet the time course of ChAT-CKO abnormalities (beginning during development) differ from motor neuron and neuromuscular disease models, in which behavioral phenotypes typically emerge in adulthood (9–11 months of age; (Dickinson and Meikle, 1973; Bridges et al., 1992; Deconinck et al., 1997; Grady et al., 1997; Laws and Hoey, 2004; Liu et al., 2016; Sopher et al., 2004; Monks et al., 2007). Early motor behavioral manifestations also occur in Dlx-CKO and other DYT1 models, emphasizing the importance of torsinA function during development and maturation at behavioral (Pappas et al., 2015; Liang et al., 2014), cellular (Pappas et al., 2018), and molecular levels (Tanabe et al., 2016).

These findings establish a cell autonomous requirement of torsinA for the normal function and survival of distinct populations of cholinergic neurons. Comparison of basic cellular properties between susceptible and invulnerable cholinergic neuron populations does not identify obvious patterns driving selective vulnerability (Tables 2 and 3). Within the striatum, dorsal ChI are highly vulnerable to cell death, while ventral ChI are spared. It is unclear whether molecular differences within different ChI populations drive vulnerability, or if differences in connectivity or response to inputs contributes to their loss; these possibilities are not mutually exclusive. While often considered a single neuronal class, an existing and enlarging literature demonstrates that dorsal and ventral striatal ChI exhibit significant differences in morphology, regulation, and receptor expression (reviewed in [Gonzales and Smith, 2015]), as well as differing firing patterns during behavioral tasks (Yarom and Cohen, 2011) and responses to serotonergic input (Virk et al., 2016). These differences implicate the presence of multiple ChI subclasses, though it is important to note that the spared ‘ventral’ population here represents the ventral part of the dorsal striatum, not the nucleus accumbens. Thalamostriatal and corticostriatal input is highly topographic (Alexander et al., 1986; Smith et al., 2004), raising the possibility that aberrant input from different thalamic nuclei or cortical regions (or aberrant response to that input) could alter the susceptibility of dorsal vs ventral ChI. It is likely that a combination of these and other factors plays a role in the differential susceptibility of cholinergic neuronal populations, including their molecular profiles (e.g., protective factors in some neurons, susceptibility factors in others), the response to afferent inputs, and their inherent physiological properties.

These studies greatly strengthen the connection between torsinA and cholinergic dysfunction, demonstrating that specific cholinergic populations exhibit a cell autonomous selective vulnerability to torsinA deficiency, while others – basal forebrain and ventral striatum – are spared. These findings open novel avenues of study aimed at defining the molecular mechanisms responsible for this cell autonomous selective vulnerability, and circuit-level analyses to ameliorate the effects of cholinergic neurotransmission abnormalities.

All data generated during this study are included in the manuscript and supporting files

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Author details

1. Samuel S Pappas

   Department of Neurology, University of Michigan, Ann Arbor, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6980-2058

2. Jay Li

   1. Department of Neurology, University of Michigan, Ann Arbor, United States
   2. Cell and Molecular Biology Program, University of Michigan, Ann Arbor, United States

   Contribution

   Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8146-4450

3. Tessa M LeWitt

   Department of Neurology, University of Michigan, Ann Arbor, United States

   Contribution

   Formal analysis, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

4. Jeong-Ki Kim

   1. Department of Cell Biology, Columbia University Medical Center, New York, United States
   2. Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, United States
   3. Department of Pathology, Columbia University Medical Center, New York, United States

   Contribution

   Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0218-1215

5. Umrao R Monani

   1. Department of Cell Biology, Columbia University Medical Center, New York, United States
   2. Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, United States
   3. Department of Pathology, Columbia University Medical Center, New York, United States

   Contribution

   Resources, Supervision, Funding acquisition, Writing—review and editing

   Competing interests

   No competing interests declared

6. William T Dauer

   1. Department of Neurology, University of Michigan, Ann Arbor, United States
   2. Cell and Molecular Biology Program, University of Michigan, Ann Arbor, United States
   3. Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing—review and editing

   For correspondence

   dauer@med.umich.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1775-7504

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