Striatal Cholinergic Cell Ablation Attenuates l-DOPA Induced Dyskinesia in Parkinsonian Mice

Won, Lisa; Ding, Yunmin; Singh, Pardeep; Kang, Un Jung

doi:10.1523/jneurosci.2888-13.2014

Cited by 75 publications

(93 citation statements)

References 33 publications

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“…Both the altered ChI physiology and behavioral expression of LID are dependent on the mitogen-activated protein kinase signaling transduction pathway (Ding et al, 2011). Furthermore, ablation of striatal ChIs reduces LID (Won et al, 2014). These data indicate that modulation of striatal cholinergic tone may be a potential target for LID therapy.…”

Section: Introductionmentioning

confidence: 81%

“…In the mouse, these cholinergic interneurons (ChIs) comprise between 1 and 2% of all striatal cells, but through their extensive arborization, they affect the activity of both dopaminergic nerve terminals and the medium spiny neurons that encode striatal output (Bolam et al, 1984;Calabresi et al, 2000;Threlfell et al, 2012;Wilson et al, 1990). Dysfunction in striatal cholinergic tone has been observed in movement disorders including dystonia and Huntington's disease (Farrar et al, 2011;Sciamanna et al, 2012), and our previous research implicates a role for a change in ChI physiology in LID (Ding et al, 2011;Won et al, 2014). In extracellular recordings of ChI firing rate, enhanced baseline excitability and hypersensitivity to dopamine are both associated with LID in mouse models of PD.…”

Section: Introductionmentioning

confidence: 94%

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Enhanced histamine H2 excitation of striatal cholinergic interneurons in l-DOPA-induced dyskinesia

Lim

Xia

Ding

et al. 2015

Neurobiology of Disease

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Levodopa is the most effective therapy for the motor deficits of Parkinson's disease (PD), but long term treatment leads to the development of L-DOPA-induced dyskinesia (LID). Our previous studies indicate enhanced excitability of striatal cholinergic interneurons (ChIs) in mice expressing LID and reduction of LID when ChIs are selectively ablated. Recent gene expression analysis indicates that stimulatory H2 histamine receptors are preferentially expressed on ChIs at high levels in the striatum, and we tested whether a change in H2 receptor function might contribute to the elevated excitability in LID. Using two different mouse models of PD (6-hydroxydopamine lesion and Pitx3(ak/ak) mutation), we chronically treated the animals with either vehicle or l-DOPA to induce dyskinesia. Electrophysiological recordings indicate that histamine H2 receptor-mediated excitation of striatal ChIs is enhanced in mice expressing LID. Additionally, H2 receptor blockade by systemic administration of famotidine decreases behavioral LID expression in dyskinetic animals. These findings suggest that ChIs undergo a pathological change in LID with respect to histaminergic neurotransmission. The hypercholinergic striatum associated with LID may be dampened by inhibition of H2 histaminergic neurotransmission. This study also provides a proof of principle of utilizing selective gene expression data for cell-type-specific modulation of neuronal activity.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 94%

Enhanced histamine H2 excitation of striatal cholinergic interneurons in l-DOPA-induced dyskinesia

Lim

Xia

Ding

et al. 2015

Neurobiology of Disease

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“…Given the influence that small populations of neurons such as cholinergic interneurons have with respect to dyskinesia (Ding et al, 2011;Won et al, 2014), extensive further study is required, focussing on the contribution of single populations of cells to the overall gene expression pattern. between groups were assessed using a Baggerly test (Baggerly et al, 2003) and the threshold for a significant difference was a Benjamini and Hochberg adjusted p-value of <0.05.…”

Section: Discussionmentioning

confidence: 99%

Striatal mRNA expression patterns underlying peak dose l-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

et al. 2016

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L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of ParkinsonÕs disease. With prolonged treatment (≥5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step towards developing treatments for this debilitating side effect. We used the 6-OHDA rat model of ParkinsonÕs disease treated with a three week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, nondyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 minutes after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence. ¥ Cytoskeletal elements present a potential target for treatments to prevent or ameliorate L-DOPA-induced dyskinesia.

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“…These mice are fertile and easy to maintain. Additionally, in Pitx3Null mice, L-dopa stimulates both normal horizontal movements and also upward movements not seen in Pitx3WT mice (Ding et al, 2007(Ding et al, , 2011Hwang et al, 2005;Solís et al, 2015;Won et al 2014). However, since most nigral DA neurons are already lost during the perinatal period in Pitx3Null mice (van den Munckhof et al, 2003), there is a possibility that a developmental abnormality may be responsible for the L-dopa-induced upward movements, potentially confounding data interpretation and limiting the utility of this mouse model.…”

Section: Introductionmentioning

confidence: 94%

“…After 2 weeks of recovery from the lesion surgery, mice (n¼ 5) were tested for their motor response to L-dopa [10 mg/kgþ5 mg/kg benserazide, injected intraperitoneally (IP)]. Although already complex, the response to the first dose of L-dopa is more directly related to the DA loss-induced DA receptor supersensitivity ; whereas, after repeated L-dopa injection, additional complex processes such as priming are also activated (Calabresi et al, 2010;Ding et al, 2011;Nadjar et al, 2009;Won et al 2014). Thus, this study focused on the motor response to the first injection of L-dopa. During the baseline, the 5 mice that received an injection of 6-OHDA into their right MFB displayed some ipsilateral (ipsiversive) turning toward the lesioned side, but no other overt abnormality in their natural locomotion, fully consistent with the literature (Schwarting and Huston, 1996).…”

Section: 1mentioning

confidence: 99%

Similar l -dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation

Sagot

Zhou

2015

Brain Research

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Striatal Cholinergic Cell Ablation Attenuates l-DOPA Induced Dyskinesia in Parkinsonian Mice

Cited by 75 publications

References 33 publications

Enhanced histamine H2 excitation of striatal cholinergic interneurons in l-DOPA-induced dyskinesia

Enhanced histamine H2 excitation of striatal cholinergic interneurons in l-DOPA-induced dyskinesia

Striatal mRNA expression patterns underlying peak dose l-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

Similar l -dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation

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