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

Choi, Se Joon; Ma, Thong; Ding, Yunmin; Cheung, T. H. C.; Joshi, Neal; Sulzer, David; Mosharov, Eugene V.; Kang, Un Jung

doi:10.7554/elife.56920

Cited by 40 publications

(38 citation statements)

References 72 publications

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“…In addition, chronic L -DOPA administration enhanced baseline and DA-induced firing rates compared with chronic saline treatment in striatal ChIs of Pitx3 –/– mice ( Ding et al, 2011 ). The follow-up study by the same group showed that both hyperpolarization–activation cyclic nucleotide-gated and small conductance calcium-activated potassium (SK) channels mediate the change of ChI firing rates in response to chronic L -DOPA treatment ( Choi et al, 2020 ).…”

Section: Theoretic Models Of Bg In Lidmentioning

confidence: 99%

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

et al. 2021

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L-DOPA is the criterion standard of treatment for Parkinson disease. Although it alleviates some of the Parkinsonian symptoms, long-term treatment induces L-DOPA–induced dyskinesia (LID). Several theoretical models including the firing rate model, the firing pattern model, and the ensemble model are proposed to explain the mechanisms of LID. The “firing rate model” proposes that decreasing the mean firing rates of the output nuclei of basal ganglia (BG) including the globus pallidus internal segment and substantia nigra reticulata, along the BG pathways, induces dyskinesia. The “firing pattern model” claimed that abnormal firing pattern of a single unit activity and local field potentials may disturb the information processing in the BG, resulting in dyskinesia. The “ensemble model” described that dyskinesia symptoms might represent a distributed impairment involving many brain regions, but the number of activated neurons in the striatum correlated most strongly with dyskinesia severity. Extensive evidence for circuit mechanisms in driving LID symptoms has also been presented. LID is a multisystem disease that affects wide areas of the brain. Brain regions including the striatum, the pallidal–subthalamic network, the motor cortex, the thalamus, and the cerebellum are all involved in the pathophysiology of LID. In addition, although both amantadine and deep brain stimulation help reduce LID, these approaches have complications that limit their wide use, and a novel antidyskinetic drug is strongly needed; these require us to understand the circuit mechanism of LID more deeply.

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Section: Theoretic Models Of Bg In Lidmentioning

confidence: 99%

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

et al. 2021

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“…17 However, ex vivo studies in rodent models of PD have found no or modest changes of intrinsic tonic activity in SCINs 14,18,19 that can be partially reverted by L-dopa treatment. 20 Because PD becomes seriously debilitating when motor fluctuations and LID emerge, detailed studies in the off-state of L-dopa medication are needed. If chronic L-dopa exposure further disrupts SCIN activity in this condition, then SCIN potential as a therapeutic target to treat PD and LID increases.…”

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confidence: 99%

“…In vivo studies found that striatal tonically active neurons (putative SCINs) exhibit enhanced spontaneous oscillatory activity in parkinsonian monkeys that persists during the off‐state of l ‐dopa medication 17 . However, ex vivo studies in rodent models of PD have found no or modest changes of intrinsic tonic activity in SCINs 14,18,19 that can be partially reverted by l ‐dopa treatment 20 . Because PD becomes seriously debilitating when motor fluctuations and LID emerge, detailed studies in the off‐state of l ‐dopa medication are needed.…”

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confidence: 99%

Levodopa Causes Striatal Cholinergic Interneuron Burst‐Pause Activity in Parkinsonian Mice

et al. 2021

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A BS TRACT: Background: Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa-induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal-related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative. Therefore, unraveling the mechanisms causing pathological cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia may provide new molecular therapeutic targets. Methods: We used ex vivo electrophysiological recordings combined with pharmacological and morphological studies to investigate the intrinsic alterations of cholinergic interneurons in the 6-hydroxydopamine mouse model of PD treated with levodopa. Results: Cholinergic interneurons exhibit pathological burst-pause activity in the parkinsonian "off levodopa" state. This is mediated by a persistent ligand-independent activity of dopamine D1/D5 receptor signaling, involving a cyclic adenosine monophosphate (cAMP) pathway. Dysregulation of membrane ion channels that results in increased inward-rectifier potassium type 2 (Kir2) and decreased leak currents causes the burst pause activity, which can be dampened by pharmacological inhibition of intracellular cAMP. A single challenge with a dyskinetogenic dose of levodopa is sufficient to induce persistent cholinergic interneuron burst-pause firing. Conclusion: Our data unravel a mechanism causing aberrant cholinergic interneuron burst-pause activity in parkinsonian mice treated with levodopa. Targeting D5-cAMP signaling and the regulation of Kir2 and leak channels may alleviate parkinsonism and dyskinesia by restoring normal cholinergic interneuron function.

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“…The universality and nonselective cation permeability make HCN channels indispensable for cell excitability. Not only in pyramidal neurons, interneurons excitability homeostasis disorder also can trigger psychosis[51, 52]. Simultaneously, HCN channels engage on intracellular cascade reaction, like work as a downstream of some neurotransmitter receptors such as alpha-2 (α 2 ) adrenergic receptor, and the location of HCN channels in post-synapse membrane also facilitate they involve in synaptic signaling[28].…”

Section: Discussionmentioning

confidence: 99%

Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

Cai

Liu

et al. 2021

Preprint

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in neurons in the central nervous system. It has been documented that HCN channels regulate the intrinsic excitability of pyramidal cells in the medial prefrontal cortex (mPFC) of rats. Here, we report that HCN channels limited GABAergic transmission onto pyramidal cells in the mPFC. Pharmacological block of HCN channels resulted in a significant increase in the frequency of both spontaneous and miniature inhibitory postsynaptic currents (IPSCs) in mPFC pyramidal cells. Such facilitation effect on mIPSCs required presynaptic Ca2+ influx and reversed by high-dose cAMP. Such facilitation did not exist in the presence of the T-type Ca2+ channel selective blockers. Immunofluorescence staining revealed that HCN channels expressed in presynaptic GABAergic terminals, as well as in both soma and neurite of parvalbumin-expressing (PV-expressing) basket cells in the mPFC. The present results indicate that HCN channels in GABAergic interneurons, most likely PV-expressing basket cells, constrain inhibitory control over layer 5-6 pyramidal cells through restricting presynaptic Ca2+ entry.

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

Cited by 40 publications

References 72 publications

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

Levodopa Causes Striatal Cholinergic Interneuron Burst‐Pause Activity in Parkinsonian Mice

Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

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