Striatal synaptic adaptations in Parkinson's disease

Shen, Weisen; Zhai, Shenyu; Surmeier, D. James

doi:10.1016/j.nbd.2022.105686

Cited by 45 publications

(34 citation statements)

References 190 publications

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“…In the other branch of our classification, we find the two populations representing the most abundant interneuron classes: PTHLH and TAC3, together with the well-described and scarce cholinergic cells (CHAT), which have already been thoroughly characterized in the literature 3,25,46,47 . Both PTHLH and TAC3 populations further split into two subclasses of unequal proportions: PTHLH and PTHLH/MOXD1, and TAC3 and TAC3/SEMA3A, respectively.…”

Section: Discussionmentioning

confidence: 82%

“…The CN is mainly responsible for eye movement and cognitive functions, the Pu for motor control, learning and auditory responses, and the ventral striatum is related to limbic functions such as reward and motivation. Dysfunction of the striatum is a key feature of neurodegenerative disorders such as Parkinson’s and Huntington’s diseases 2,3,4,5 as well as of psychiatric conditions such as obsessive-compulsive disorder and schizophrenia 6,7,8 .…”

Section: Introductionmentioning

confidence: 99%

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Interneuron diversity in the human dorsal striatum

Garma

Harder

Barba-Reyes

et al. 2023

Preprint

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Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangle the complex neurological and psychiatric diseases affecting this brain structure. We performed single-nucleus RNA-sequencing (snRNA-seq) of postmortem human caudate nucleus (CN) and putamen (Pu) samples to elucidate the diversity and abundance of interneuron populations and their transcriptional structure in the human dorsal striatum. We propose a new taxonomy of striatal interneurons with eight main classes. We provide specific markers for all subclasses and validated some of them with quantitative in situ fluorescence hybridization, such as a novel PTHLH-expressing population that exhibits different abundance and gene expression between CN and Pu. For the most abundant interneuron populations in human striatum, PTHLH and TAC3, we found matching known mouse interneuron populations based on key functional genes such as ion channels and synaptic receptors. Remarkably, human TAC3 and mouse Th populations share important similarities including the expression of the neuropeptide tachykinin 3. Finally, we were able to integrate our dataset with several prior smaller human striatal snRNA-seq studies, thus supporting the generalizability of this new harmonized taxonomy.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Interneuron diversity in the human dorsal striatum

Garma

Harder

Barba-Reyes

et al. 2023

Preprint

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“…Striatal cholinergic INs are also thought to play a crucial role in the emergence of L-DOPA induced dyskinesias (LIDs), a severe side-effect of prolonged L-DOPA medication ( Shen et al, 2022 ). The potential role of SHH signaling in the regulation of striatal cholinergic IN physiology prompted ( Malave et al, 2021 ) to test whether the acute or chronic co-application of a SHH agonist (SAG or purmorphamine) or antagonist (cyclopamine) during L-DOPA treatment would attenuate or increase, respectively, the appearance of LIDs in mouse and primate PD models.…”

Section: Developmental Factors Required For Mda Neuron Survival In Th...mentioning

confidence: 99%

Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

Prakash

2022

Front. Mol. Neurosci.

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The degeneration of dopaminergic and other neurons in the aging brain is considered a process starting well beyond the infantile and juvenile period. In contrast to other dopamine-associated neuropsychiatric disorders, such as schizophrenia and drug addiction, typically diagnosed during adolescence or young adulthood and, thus, thought to be rooted in the developing brain, Parkinson’s Disease (PD) is rarely viewed as such. However, evidences have accumulated suggesting that several factors might contribute to an increased vulnerability to death of the dopaminergic neurons at an already very early (developmental) phase in life. Despite the remarkable ability of the brain to compensate such dopamine deficits, the early loss or dysfunction of these neurons might predispose an individual to suffer from PD because the critical threshold of dopamine function will be reached much earlier in life, even if the time-course and strength of naturally occurring and age-dependent dopaminergic cell death is not markedly altered in this individual. Several signaling and transcriptional pathways required for the proper embryonic development of the midbrain dopaminergic neurons, which are the most affected in PD, either continue to be active in the adult mammalian midbrain or are reactivated at the transition to adulthood and under neurotoxic conditions. The persistent activity of these pathways often has neuroprotective functions in adult midbrain dopaminergic neurons, whereas the reactivation of silenced pathways under pathological conditions can promote the survival and even regeneration of these neurons in the lesioned or aging brain. This article summarizes our current knowledge about signaling and transcription factors involved in midbrain dopaminergic neuron development, whose reduced gene dosage or signaling activity are implicated in a lower survival rate of these neurons in the postnatal or aging brain. It also discusses the evidences supporting the neuroprotection of the midbrain dopaminergic system after the external supply or ectopic expression of some of these secreted and nuclear factors in the adult and aging brain. Altogether, the timely monitoring and/or correction of these signaling and transcriptional pathways might be a promising approach to a much earlier diagnosis and/or prevention of PD.

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“…A growing body of evidence suggests that nitric oxide (NO) plays a role in the maintenance of LIDs [21][22][23][24][25][26], since it is synthesized in striatal interneurons by NO synthase (NOS) [27][28][29]. NO modulates the striatal function, changing its input-output relationship and producing a functionally significant impact on target neurons [30][31][32][33]. It has been suggested that (i) NO synthesis increases in the basal ganglia in experimental parkinsonism and in chronic treatment with L-DOPA [34][35][36][37], and (ii) nitrate concentrations and nitrite levels are high in the cerebrospinal fluid of patients with Parkinson's disease receiving dopamine replacement [38] and in patients with PD and LIDs [39].…”

Section: Introductionmentioning

confidence: 99%

7-Nitroindazole reduces L-DOPA-induced dyskinesias in non-human Parkinsonian primate

Herrero,

Yuste,

Cuenca-Bermejo

et al. 2023

Open Biol.

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Nitric oxide (NO) plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). The objective of this study was to ascertain whether the NO synthase inhibitor, 7-nitroindazole (7-NI), is able to reduce L-DOPA-induced dyskinesias (LIDs) in a non-human primate model of PD chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Six Parkinsonian macaques were treated daily with L-DOPA for 3–4 months until they developed LIDs. Three animals were then co-treated with a single dose of 7-NI administered 45 min before each L-DOPA treatment. Dyskinetic MPTP-treated monkeys showed a significant decrease in LIDs compared with their scores without 7-NI treatment ( p < 0.05). The anti-Parkinsonian effect of L-DOPA was similar in all three monkeys with and without 7-NI co-treatment. This improvement was significant with respect to the intensity and duration of LIDs while the beneficial effect of L-DOPA treatment was maintained and could represent a promising therapy to improve the quality of life of PD patients.

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Striatal synaptic adaptations in Parkinson's disease

Cited by 45 publications

References 190 publications

Interneuron diversity in the human dorsal striatum

Interneuron diversity in the human dorsal striatum

Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

7-Nitroindazole reduces L-DOPA-induced dyskinesias in non-human Parkinsonian primate

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