Thalamic degeneration in MPTP-treated Parkinsonian monkeys: impact upon glutamatergic innervation of striatal cholinergic interneurons

Villalba, Rosa M.; Paré, Jean‐François; Lee, Solah; Lee, Sol; Smith, Yoland

doi:10.1007/s00429-019-01967-w

Cited by 13 publications

(14 citation statements)

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“…Earlier studies addressing the impact of DA depletion on the numbers of two specific striatal interneurons in primates have shown, in line with the present findings, that no major changes are present in the densities of striatal Cr+ and ChAT+ interneurons in MPTPtreated macaques [53,64]. In rodents, however, opposite results regarding the Cr+ interneurons in the DA-depleted striatum have been published: transient increase [65] or a decrease [66,67].…”

Section: Interneurons In the Healthy Striatumsupporting

confidence: 90%

Neuron types in the primate striatum: Stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys

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Trigo‐Damas

Obeso

et al. 2022

Neuropathology Appl Neurobio

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Aims:The striatum is mainly composed of projection neurons. It also contains interneurons, which modulate and control striatal output. The aim of the present study was to assess the percentages of projection neurons and interneuron populations in the striatum of control monkeys and of parkinsonian monkeys.Methods: Unbiased stereology was used to estimate the volume density of every neuron population in the caudate, putamen and ventral striatum of control monkeys and of monkeys treated with MPTP, which results in striatal dopamine depletion. The various neuron population phenotypes were identified by immunohistochemistry. All analyses were performed within the same subjects using similar processing and analysis parameters, thus allowing for reliable data comparisons.Results: In control monkeys, the projection neurons, which express the dopamineand-cAMP-regulated-phosphoprotein, 32-KDa (DARPP-32

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Section: Interneurons In the Healthy Striatumsupporting

confidence: 90%

Neuron types in the primate striatum: Stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys

provided

Trigo‐Damas

Obeso

et al. 2022

Neuropathology Appl Neurobio

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“…We conclude that a great part of CINs hyperactivity found after DA depletion is due to glutamatergic transmission either from the cortex or thalamus (e.g., Arias-García et al, 2017 ). Because in control non-stimulated conditions glutamatergic blockade has non-significant actions, it is inferred that a change in synaptic glutamatergic transmission due to DA depletion affects CINs activity ( Villalba et al, 2015 , 2019 ; Parker et al, 2016 ; Aceves-Buendia et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Padilla‐Orozco

Duhne

Fuentes-Serrano

et al. 2022

Front. Synaptic Neurosci.

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Parkinson’s disease is a neurodegenerative ailment generated by the loss of dopamine in the basal ganglia, mainly in the striatum. The disease courses with increased striatal levels of acetylcholine, disrupting the balance among these modulatory transmitters. These modifications disturb the excitatory and inhibitory balance in the striatal circuitry, as reflected in the activity of projection striatal neurons. In addition, changes in the firing pattern of striatal tonically active interneurons during the disease, including cholinergic interneurons (CINs), are being searched. Dopamine-depleted striatal circuits exhibit pathological hyperactivity as compared to controls. One aim of this study was to show how striatal CINs contribute to this hyperactivity. A second aim was to show the contribution of extrinsic synaptic inputs to striatal CINs hyperactivity. Electrophysiological and calcium imaging recordings in Cre-mice allowed us to evaluate the activity of dozens of identified CINs with single-cell resolution in ex vivo brain slices. CINs show hyperactivity with bursts and silences in the dopamine-depleted striatum. We confirmed that the intrinsic differences between the activity of control and dopamine-depleted CINs are one source of their hyperactivity. We also show that a great part of this hyperactivity and firing pattern change is a product of extrinsic synaptic inputs, targeting CINs. Both glutamatergic and GABAergic inputs are essential to sustain hyperactivity. In addition, cholinergic transmission through nicotinic receptors also participates, suggesting that the joint activity of CINs drives the phenomenon; since striatal CINs express nicotinic receptors, not expressed in striatal projection neurons. Therefore, CINs hyperactivity is the result of changes in intrinsic properties and excitatory and inhibitory inputs, in addition to the modification of local circuitry due to cholinergic nicotinic transmission. We conclude that CINs are the main drivers of the pathological hyperactivity present in the striatum that is depleted of dopamine, and this is, in part, a result of extrinsic synaptic inputs. These results show that CINs may be a main therapeutic target to treat Parkinson’s disease by intervening in their synaptic inputs.

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“…Anticholinergic actions at extrastriatal sites impair short term memory and frontal lobe function in patients and may exacerbate gait and postural deficits (Katzenschlager et al., 2003; Perez‐Lloret & Barrantes, 2016). Importantly, there is evidence that cholinergic neurons in the pedunculopontine tegmental nucleus and basal forebrain degenerate in patients and animal models of PD (Hirsch, Graybiel, Duyckaerts, & Javoy‐Agid, 1987; Zweig, Jankel, Hedreen, Mayeux, & Price, 1989; Shinotoh et al., 1999; Villalba, Pare, Lee, Lee, & Smith, 2019; Tubert, Galtieri, & Surmeier, 2019), leading to reduced acetylcholine levels at the cerebral cortex and thalamus that contribute to the cognitive and gait deficits observed in patients (Düzel et al., 2010; Fernández et al., 2011; Hall, Echt, Wolf, & Rogers, 2011; Sarter, Albin, Kucinski, & Lustig, 2014; Tubert et al., 2019; Wolf et al., 2014). Brain imaging studies support the existence of such hypocholinergic state in the thalamus and cortex (Bohnen et al., 2012, 2015; Bohnen, Müller, & Frey, 2017; Kim, Müller, Bohnen, Sarter, & Lustig, 2017; Müller et al., 2013; Ray et al., 2018).…”

Section: Anticholinergic Therapy In Parkinson's Diseasementioning

confidence: 99%

“…Moreover, Ikarashi and Cao with their respective colleagues showed through microdialysis and liquid chromatography experiments that striatal extracellular acetylcholine is increased in PD rodent models (Cao et al., 2012; Ikarashi et al., 1997) and that it gradually increases after the lesion of dopaminergic nigrostriatal neurons (Cao et al., 2012). In contrast to the degeneration observed in cholinergic projection neurons of the basal forebrain and mesopontine tegmentum, the density of ChIs is increased in the caudate nucleus of parkinsonian monkeys (Petryszyn, Di Paolo, Parent, & Parent, 2016; Villalba et al., 2019). The advancement of fluorescent acetylcholine markers allowing to measure acetylcholine release in in vivo and ex vivo preparations will probably give us a better understanding of the hypercholinergic state dynamics.…”

Section: The Striatal Hypercholinergic Statementioning

confidence: 99%

What’s wrong with the striatal cholinergic interneurons in Parkinson’s disease? Focus on intrinsic excitability

Tubert

Murer

2020

Eur J of Neuroscience

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Parkinson's disease (PD) is characterized by a degeneration of nigrostriatal dopaminergic neurons that results in a hypercholinergic state in the striatum. This hypercholinergic state contributes to the clinical signs of PD. However, the mechanisms that underlie this state remain unknown. Cholinergic interneurons (ChIs) are the main source of acetylcholine in the striatum. Many studies have highlighted the importance of their normal physiological activity to guarantee a normal motor control and goal-directed behaviour. Moreover, recent studies with optogenetic and chemogenetic approaches have shown that reducing ChIs activity ameliorates parkinsonian symptoms and modifies L-dopa induced dyskinesia in PD animal models. Here, we review the described alterations in ChIs physiology that may contribute to a hypercholinergic state in PD. The best-established finding is an increase of ChIs intrinsic membrane excitability after dopaminergic denervation of striatum. Understanding the molecular basis of ChIs dysfunction in PD could help to develop new therapeutic tools to restore their normal activity and decrease parkinsonian symptoms, improving life quality of PD patients.

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Thalamic degeneration in MPTP-treated Parkinsonian monkeys: impact upon glutamatergic innervation of striatal cholinergic interneurons

Cited by 13 publications

References 137 publications

Neuron types in the primate striatum: Stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys

Neuron types in the primate striatum: Stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

What’s wrong with the striatal cholinergic interneurons in Parkinson’s disease? Focus on intrinsic excitability

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