Morphological and electrophysiological changes in intratelencephalic-type pyramidal neurons in the motor cortex of a rat model of levodopa-induced dyskinesia

Ueno, Takayoshi; Yamada, Jun; Nishijima, Haruo; Arai, Akira; Migita, Keisuke; Baba, Masayuki; Ueno, Shinji; Tomiyama, Masahiko

doi:10.1016/j.nbd.2013.12.014

Cited by 35 publications

(54 citation statements)

References 45 publications

(71 reference statements)

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“…In addition, accumulating evidence indicates a role for other brain regions. This includes the cortex, with LIDs correlating with supersensitive excitatory transmission at corticostriatal synapses (Ueno et al, 2014) and high-frequency cortical oscillations (Richter et al, 2013). The cerebellum also plays a role in LIDs possibly via the primary motor cortex (Kishore and Popa, 2014; Kishore et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Bordia

Perez

Heiss

et al. 2016

Neurobiology of Disease

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L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization.

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Section: Discussionmentioning

confidence: 99%

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Bordia

Perez

Heiss

et al. 2016

Neurobiology of Disease

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“…Severe loss of nigral dopaminergic neurons, leading to a dramatic striatal dopamine depletion, is an essential precondition for the expression of LID 8,9 . However, hyperkinesias only occur if associated with subtle alterations of the dendritic spines of cortical and striatal neurons 10,11 .…”

mentioning

confidence: 99%

Hyperkinetic disorders and loss of synaptic downscaling

Calabresi

Pisani

Rothwell³

et al. 2016

Nat Neurosci

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Recent clinical and preclinical studies have shown that hyperkinetic disorders such as Huntington's disease, dystonia and l-DOPA-induced dyskinesia in Parkinson's disease are all characterized by loss of the ability to reverse synaptic plasticity and an associated increase in the excitability of excitatory neuronal inputs to a range of cortical and subcortical brain areas. Moreover, these changes have been detected in humans with hyperkinetic disorders either via direct recordings from implanted deep brain electrodes or noninvasively using transcranial magnetic stimulation. Here we discuss the mechanisms underlying the loss of bidirectional plasticity and the possibility that future interventions could be devised to reverse these changes in patients with hyperkinetic movement disorders.

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“…It has been reported that dSPNs appear to play an important role in the development of LID (Picconi et al, 2003; Shen et al, 2015). In a previous study, we found enlargement of IT neuron spines in a LID model rat and proposed that IT neurons in the M1 may store abnormal information resulting in LID (Ueno et al, 2014). Furthermore, IT neurons in the M1 of the LID rat model displayed increased amplitudes of miniature excitatory postsynaptic currents (Ueno et al, 2014).…”

Section: Introductionmentioning

confidence: 82%

Spine Enlargement of Pyramidal Tract-Type Neurons in the Motor Cortex of a Rat Model of Levodopa-Induced Dyskinesia

et al. 2017

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Growing evidence suggests that abnormal synaptic plasticity of cortical neurons underlies levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). Spine morphology reflects synaptic plasticity resulting from glutamatergic transmission. We previously reported that enlargement of the dendritic spines of intratelencephalic-type (IT) neurons in the primary motor cortex (M1) is linked to the development of LID. However, the relevance of another M1 neuron type, pyramidal-tract (PT) neurons, to LID remains unknown. We examined the morphological changes of the dendritic spines of M1 PT neurons in a rat model of LID. We quantified the density and size of these spines in 6-hydroxydopamine-lesioned rats (a model of PD), 6-hydroxydopamine-lesioned rats chronically treated with levodopa (a model of LID), and control rats chronically treated with levodopa. Dopaminergic denervation alone had no effect on spine density and head area. However, the LID model showed significant increases in the density and spine head area and the development of dyskinetic movements. In contrast, levodopa treatment of normal rats increased spine density alone. Although, chronic levodopa treatment increases PT neuron spine density, with or without dopaminergic denervation, enlargement of PT neuron spines appears to be a specific feature of LID. This finding suggests that PT neurons become hyperexcited in the LID model, in parallel with the enlargement of spines. Thus, spine enlargement, and the resultant hyperexcitability of PT pyramidal neurons, in the M1 cortex might contribute to abnormal cortical neuronal plasticity in LID.

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Morphological and electrophysiological changes in intratelencephalic-type pyramidal neurons in the motor cortex of a rat model of levodopa-induced dyskinesia

Cited by 35 publications

References 45 publications

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Hyperkinetic disorders and loss of synaptic downscaling

Spine Enlargement of Pyramidal Tract-Type Neurons in the Motor Cortex of a Rat Model of Levodopa-Induced Dyskinesia

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