Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice

Borgkvist, Anders; Avegno, Elizabeth M.; Wong, Minerva Y.; Kheirbek, Mazen A.; Sonders, Mark S.; Hen, René; Sulzer, David

doi:10.1016/j.neuron.2015.08.022

Cited by 63 publications

(77 citation statements)

References 61 publications

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“…Importantly, sham animals, which showed only a slight increase in motor activity during light stimulation, did not show higher c‐Fos expression in the ChR2 hemisphere. Together with previous studies showing limited effects of backpropagating action potentials in dMSN dendrites (Day, Wokosin, Plotkin, Tian, & Surmeier, ), and studies showing plasticity at inhibitory synapses in the SNr in both animal PD models and patients (Borgkvist et al, ; Milosevic et al, ; Yamamoto et al, ), the data favour the view that local plasticity at striatonigral synapses play a role in our findings.…”

Section: Discussionsupporting

confidence: 90%

“…Pioneering studies in mice have shown that optogenetic stimulation of dMSN cell bodies (Kravitz et al, ) and axon terminals (Borgkvist et al, ) causes an increase in normal motor activity and an improvement of Parkinson‐like motor symptoms. Improvement of symptoms is linked to inhibition of SNr neurons by GABA released from striatonigral axon terminals (Borgkvist et al, ; Freeze et al, ), as predicted by classical basal ganglia models (Albin, Young, & Penney, ). It is also in line with electrophysiological evidence from studies that find inhibition of GPi and SNr neurons in animal models of PD and patients treated with L‐DOPA and mixed D 1 /D 2 receptor agonists, such as apomorphine, at doses that reduce parkinsonian symptoms (Boraud et al, ; Filion et al, ; Lozano et al, ; Papa et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Keifman

Ruiz-DeDiego

Pafundo

et al. 2019

British J Pharmacology

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Background and Purpose L‐DOPA‐induced dyskinesia (LID) remains a major complication of L‐DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L‐DOPA. Experimental Approach Adult C57BL6 mice were lesioned with 6‐hydroxydopamine in the medial forebrain bundle. Channel rhodopsin was expressed in striatonigral terminals by ipsilateral striatal injection of adeno‐associated viral particles under the CaMKII promoter. Optic fibres were implanted on the ipsilateral SNr. Optical stimulation was performed before and 24 hr after three daily doses of L‐DOPA at subthreshold and suprathreshold dyskinetic doses. We also examined the combined effect of light stimulation and an acute L‐DOPA challenge. Key Results Optostimulation of striatonigral terminals inhibited SNr neurons and induced all dyskinesia subtypes (optostimulation‐induced dyskinesia [OID]) in 6‐hydroxydopamine animals, but not in sham‐lesioned animals. Additionally, chronic L‐DOPA administration sensitised dyskinetic responses to striatonigral terminal optostimulation, as OIDs were more severe 24 hr after L‐DOPA administration. Furthermore, L‐DOPA combined with light stimulation did not result in higher dyskinesia scores than OID alone, suggesting that optostimulation has a masking effect on LID. Conclusion and Implications This work suggests that striatonigral inhibition of basal ganglia output (SNr) is a decisive mechanism mediating LID and identifies the SNr as a target for managing LID.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Keifman

Ruiz-DeDiego

Pafundo

et al. 2019

British J Pharmacology

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“…However, this result cannot account for all the circuit perturbations observed in iMSN-Drd2KO mice such as the decrease in GPe firing and dMSN firing, two downstream targets of iMSNs. Recent studies have demonstrated an enhanced GABAergic tone within the basal ganglia following 6-OHDA lesion (Borgkvist et al, 2015; Fan et al, 2012). We therefore assessed the state of GABAergic transmission at the output of iMSNs.…”

Section: Resultsmentioning

confidence: 99%

Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

Lemos

Friend

Kaplan

et al. 2016

Neuron

112

164

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Summary Bradykinesia is a prominent phenotype of Parkinson’s disease, depression, and other neurological conditions. Disruption of dopamine transmission plays an important role but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson’s disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission.

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“…For example, TRAPed neurons may be particularly vulnerable to aberrant corticostriatal plasticity, which has been reported in rodent models of LID (Bagetta et al, 2012; Fieblinger et al, 2014; Picconi et al, 2003; Shen et al, 2015). Alternatively, TRAPed cells may differ from neighboring dMSNs in local inhibitory connections (Gittis et al, 2011a), synaptic output (Borgkvist et al, 2015), or sensitivity to dopamine (Heiman et al, 2014), which in turn may drive differences in behavior evoked by manipulating TRAPed versus random dMSNs. Finally, the TRAPed population included PV-positive striatal neurons and iMSNs, which may contribute to circuit dysfunction and dyskinesia.…”

Section: Discussionmentioning

confidence: 99%

A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia

Girasole

Lum

Nathaniel

et al. 2018

Neuron

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SUMMARY Parkinson’s disease is characterized by the progressive loss of midbrain dopamine neurons. Dopamine replacement therapy with levodopa alleviates parkinsonian motor symptoms but is complicated by the development of involuntary movements, termed levodopa-induced dyskinesia (LID). Aberrant activity in the striatum has been hypothesized to cause LID. Here, to establish a direct link between striatal activity and dyskinesia, we combine optogenetics and a method to manipulate dyskinesia-associated neurons, targeted recombination in active populations (TRAP). We find that TRAPed cells are a stable subset of sensorimotor striatal neurons, predominantly from the direct pathway, and that reactivation of TRAPed striatal neurons causes dyskinesia in the absence of levodopa. Inhibition of TRAPed cells, but not a nonspecific subset of direct pathway neurons, ameliorates LID. These results establish that a distinct subset of striatal neurons is causally involved in LID and indicate that successful therapeutic strategies for treating LID may require targeting functionally selective neuronal subtypes.

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Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice

Cited by 63 publications

References 61 publications

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Enhanced GABA Transmission Drives Bradykinesia Following Loss of Dopamine D2 Receptor Signaling

A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia

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