Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease

McKinley, Jonathan W.; Shi, Ziqing; Kawikova, Ivana; Hur, Matthew; Bamford, Ian J.; Devi, Suma Priya Sudarsana; Vahedipour, Annie; Darvas, Martin; Bamford, Nigel S.

doi:10.1016/j.neuron.2019.06.013

Cited by 109 publications

(129 citation statements)

References 70 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…ChIs exhibit cell autonomous firing patterns, including irregular firing with bursts and pauses (Goldberg and Wilson, 2005;Wilson, 2005;Wilson and Goldberg, 2006). Previous reports showed that DA depletion decreased the regularity of spontaneous firing and the number of bursts and pauses (McKinley et al, 2019). Consistent with these findings, we found an increase in the coefficient of variation (CV) of the instantaneous frequencies of sAP in ChIs from 6-OHDA mice, which was restored to sham control levels after chronic L-DOPA (Figure 1D).…”

Section: Changes In Chi Spontaneous Firing Rate Following Da Depletiosupporting

confidence: 90%

“…Similarly, increasing ChI firing rate by chemogenetic or optogenetic methods enhanced LID expression (Aldrin-Kirk et al, 2018;Bordia et al, 2016a), while decreasing ChI firing rate by inhibiting H2 histamine receptors that are preferentially expressed in ChIs in the striatum, attenuated LID (Lim et al, 2015). Alterations in ChI activity following DA depletion have been studied, although with conflicting results (Ding et al, 2006;Maurice et al, 2015;McKinley et al, 2019;Sanchez et al, 2011;Tubert et al, 2016). However, the basis of changes in ChI physiology resulting from chronic L-DOPA treatment of DA depleted mice have not been identified.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Choi

Ding

et al. 2020

Preprint

View full text Add to dashboard Cite

Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes are unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.

show abstract

Section: Changes In Chi Spontaneous Firing Rate Following Da Depletiosupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Choi

Ding

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Shh binding to Ptc1 relieves the inhibition of Smo [42]. [8], target CIN of the DLS [44] and degenerate in PD [32]. We found that mice with selective ablation of Shh from DAN (ShhDAN -/- [8] ShhDAN -/mice resulted in an increase in the fraction of pErk 1,2 positive CIN in the DLS, which could be normalized by SAG ( Fig.…”

Section: B)mentioning

confidence: 93%

Section: Mainmentioning

confidence: 99%

“…Unfortunately, how DAN degeneration results in aberrant CIN activity is also not well understood [30]. For example, as DA levels fall in the PD brain, cholinergic signaling strength rises [31], yet acetylcholine availability becomes reduced concomitantly with progressive DAN deficiency in murine models [32] suggesting that relative rather than absolute levels of cholinergic tone might change in PD.Recently it was found that dopaminergic co-transmission with glutamate supports the rebound of firing of CIN located in the dorso-lateral striatum (DLS) after a DA induced pause in firing [7].Since CIN express the Shh receptor Patched (Ptc1) [8], we investigated whether reduced levels of Shh expressed by DAN (ShhDAN) might play a role in LID.DAN degeneration must cause a diminishment of DA as well as ShhDAN. Therefore, L-Dopa treatment without augmenting Shh signaling must result in a drug-induced imbalance of high DA and low Shh signaling onto CIN compared to the situation in the healthy brain ( Fig.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Abnormal Involuntary Movements

Malave¹,

Zuelke²,

Starikov³

et al. 2020

Preprint

View full text Add to dashboard Cite

Our limited understanding of neuronal co-transmission complicates predicting the effects of pharmacological interventions from neuronal wiring diagrams [1, 2]. For example, dopamine neurons (DAN), whose degeneration causes the motor and cognitive deficits of Parkinson's Disease (PD) [3], communicate with all their targets by dopamine (DA) and in addition use the neurotransmitters GABA, Glutamate and secreted peptides including the morphogen Sonic Hedgehog (Shh) to signal to select subsets of neurons [4][5][6][7][8]. It is unknown whether Levodopa (L-Dopa) induced dyskinesia (LID), a debilitating side effect of DA supplementation therapy in PD [9], might appear because DAN targets become exposed to high levels of DA but diminished levels of other DAN produced signaling factors. Here we show that restoring the balance of DA and Shh signaling by agonists of the Shh signaling effector G-protein coupled receptor Smoothened (Smo [10, 11]) attenuates LID in mouse-and macaque-models of PD. Using conditional genetic loss of function approaches of pre-and post-synaptic Shh signaling we found that reducing the activity of Smo selectively in cholinergic neurons facilitates LID. Conversely, the expression of a constitutive active form of Smo (SmoM2 [12]) in cholinergic neurons is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, the acute diminishment of Shh emanating from DAN by optogenetic means in the otherwise intact brain and in the absence of L-Dopa results in LID-like abnormal involuntary movements. We reveal that Shh co-transmission counteracts DA action in a DAN target-and striatal domain-specific manner. Our results suggest an un-anticipated mechanism -reduced Shh signaling -by which DAN degeneration sensitizes PD patients to LID. We anticipate that our models provide a starting point for assessing the contributions of Shh to the "teaching" signal that emanates from DAN and testing the hypothesis that LID are caused by aberrant learning [13][14][15]. Main:Previous work has implicated aberrant cholinergic activity in LID in PD models but mechanistic details remain ill-defined since both boosting as well as inhibiting cholinergic signaling were found to attenuate LID [16][17][18][19][20][21][22]. These divergent results are likely a reflection of the post synaptic complexity of cholinergic signaling in the striatum [23]. Hence, normalizing cholinergic activity at the level of CIN themselves might prevent the formation of LID and preserve the contribution of regulated CIN activity to striatal function. In the healthy brain, DAN engage CIN as a relay hub to control striatal circuits by patterning cholinergic activity [24,25]: DA inhibits CIN through binding to D2 receptor (D2R) resulting in the pause of the "burst-pause-burst" firing pattern of CIN in response to reward-related cues or outcomes [26,27] [28,29]. Unfortunately, how DAN degeneration results in aberrant CIN activity is also not well understood [30]. For example, as DA levels fall in the PD brain, cholinergic signaling s...

show abstract

Ellagic acid mitigates rotenone‐induced damage via modulating mitochondria function in Drosophila melanogaster

Adedara

Otenaike

Farodoye

et al. 2023

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Constant, systematic exposure to rotenone has been utilized in animal models to induce Parkinsonism. Ellagic acid is a polyphenol with anti-inflammatory and antioxidative properties which is found in numerous natural fruits. Here, we investigated the therapeutic effects of ellagic acid in rotenone-induced toxicity in Drosophila melanogaster evaluating their antioxidant and mitoprotective properties.Adult flies were treated with rotenone and ellagic acid through their diet for 7 days, thereafter markers of neurotoxicity (acetylcholinesterase, monoamine oxidase, tyrosine hydroxylase), antioxidant and oxidative stress markers (hydrogen peroxide, nitric oxide, lipid peroxidation, protein carbonyl contents, catalase, total thiol, and nonprotein thiol) was measured. Mitochondrial respiration was also evaluated in the flies. Survival assay was carried out with both genders of the flies, and we observed a significant increase in the survival rate of flies exposed to both rotenone and ellagic acid when compared with the increased mortality rate in the groups exposed to rotenone alone. The impaired locomotion, altered redox status, and enzymes of neurotoxicity induced by rotenone were significantly ameliorated by ellagic acid to levels comparable to the control. In addition, rotenone-induced complex 1 inhibition and altered bioenergetic state were restored upon ellagic acid supplementation.These findings show the beneficial properties of ellagic acid against pesticides induced toxicity.

show abstract

Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease

Cited by 109 publications

References 70 publications

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Abnormal Involuntary Movements

Ellagic acid mitigates rotenone‐induced damage via modulating mitochondria function in Drosophila melanogaster

Contact Info

Product

Resources

About