Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates

Singh, Anneliese A.; Liang, Li; Kaneoke, Yoshiki; Cao, Xin; Papa, Stella M.

doi:10.1152/jn.00910.2014

Cited by 49 publications

(65 citation statements)

References 69 publications

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“…ET could, therefore, represent the "normality" status of the human SPN firing, and its comparison revealed the development of profound changes in PD. In addition, NHP with severe MPTP-induced parkinsonism exhibited striatal activity changes similar to those observed in patients with PD (18,19), thus establishing a clear parallelism between normal-to-dopamine lesion animal states and ET-to-PD human disorders. Accordingly, SPN hyperactivity and burst firing likely are abnormal neuronal activity characteristics of the parkinsonian state.…”

Section: Discussionsupporting

confidence: 53%

“…Nevertheless, studies in anesthetized hemiparkinsonian rats show higher SPN activity (16,17). In the NHP model of advanced parkinsonism that more closely reproduces PD features, SPN recordings show major activity alterations (18,19). However, it is often questionable whether large changes produced by short-term, high-toxin exposure in the animal are equivalent to the effects of slowly progressive neurodegeneration as occurs in the human disease (20).…”

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confidence: 99%

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Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson’s disease

Singh

Mewes

Gross

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Circuitry models of Parkinson's disease (PD) are based on striatal dopamine loss and aberrant striatal inputs into the basal ganglia network. However, extrastriatal mechanisms have increasingly been the focus of attention, whereas the status of striatal discharges in the parkinsonian human brain remains conjectural. We now report the activity pattern of striatal projection neurons (SPNs) in patients with PD undergoing deep brain stimulation surgery, compared with patients with essential tremor (ET) and isolated dystonia (ID). The SPN activity in ET was very low (2.1 ± 0.1 Hz) and reminiscent of that found in normal animals. In contrast, SPNs in PD fired at much higher frequency (30.2 ± 1.2 Hz) and with abundant spike bursts. The difference between PD and ET was reproduced between 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and normal nonhuman primates. The SPN activity was also increased in ID, but to a lower level compared with the hyperactivity observed in PD. These results provide direct evidence that the striatum contributes significantly altered signals to the network in patients with PD.otor features of Parkinson's disease (PD) are caused by alterations in the corticobasal ganglia-thalamic network, although the role of particular circuits is unclear (1-3). The progressive degeneration of nigral neurons that massively deplete the striatum of dopamine is at center stage. Classic circuitry models of PD are based on the dopamine-depleted striatum sending disrupted commands through medium spiny neurons, the striatal projection neurons (SPNs), into the direct and indirect output pathways (4, 5). However, the role of a dysfunctional striatum has been undermined in recent years in part due to the focus on extrastriatal mechanisms, particularly the direct cortical regulation of the subthalamic nucleus (hyperdirect pathway), and the widespread effects of dopamine depletion over basal ganglia stations (6-8). In addition, the striatal changes predicted by the model lack clear functional correlates in humans. The only available data are provided by neuroimaging and show inconsistent metabolic changes (both increased or normal activity) in the putamen of patients with PD (9). On the other hand, the molecular and physiological impact of dopamine loss on striatal outputs has been difficult to determine, given the complexity of microcircuits regulating the SPN activity. Convergent cortical, nigral, thalamic, and various interneuronal signals could variably exacerbate or compensate for the lack of dopamine modulation on SPN discharges (10).Morphological and physiological studies in animal models of PD, however, have provided significant data supporting abnormal SPN activity in the parkinsonian state. There is a major loss of dendritic spines in SPNs that is accompanied by remodeling and enlargement of postsynaptic densities of the remaining spines (11,12). Although the mechanisms underlying spine pruning and regrowth are yet unclear, ultimately, these morphological changes involve synaptic contacts and thus have ma...

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Section: Discussionsupporting

confidence: 53%

mentioning

confidence: 99%

Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson’s disease

Singh

Mewes

Gross

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, neuronal activity data were stored for offline analysis at the following time points: (1) before local injection (“pre”), (2) after local injection (“post”), (3) “on” state (onset of reversal of parkinsonism induced by L-DOPA; “on”), and (4) dyskinesias (L-DOPA-induced dyskinesias at the peak-dose effect; “dys”). Following local aCSF application (control test) that had no effect or produced very brief changes of SPN activity (pre to post), L-DOPA induced the typical responses of increased or decreased firing frequency (post to on; Figures 2A–2D) (Singh et al, 2015). In these control tests, SPN activity increased in 14 units and decreased in the other 15 units, and these firing changes correlated with the behavioral changes indicating that the animal had transitioned to the “on” state.…”

Section: Resultsmentioning

confidence: 99%

“…Such a state of high basal activity likely may interfere with the strength of DA signaling to modulate SPN excitability. Congruent with this premise, dopaminergic stimulation induces unstable changes in SPN firing frequency that are associated with dyskinesias in primates with advanced parkinsonism (Liang et al, 2008; Singh et al, 2015). Thus, SPN hyperactivity may play a primary role in the altered responses to DA replacement.…”

Section: Introductionmentioning

confidence: 99%

Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates

et al. 2018

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SUMMARY Dopamine (DA) loss in Parkinson’s disease (PD) alters the function of striatal projection neurons (SPNs) and causes motor deficits, but DA replacement can induce further abnormalities. A key pathological change in animal models and patients is SPN hyperactivity; however, the role of glutamate in altered DA responses remains elusive. We tested the effect of locally applied AMPAR or NMDAR antagonists on glutamatergic signaling in SPNs of parkinsonian primates. Following a reduction in basal hyperactivity by antagonists at either receptor, DA inputs induced SPN firing changes that were stable during the entire motor response, in clear contrast with the typically unstable effects. The SPN activity reduction over an extended putamenal area controlled the release of involuntary movements in the “on” state and therefore improved motor responses to DA replacement. These results demonstrate the pathophysiological role of upregulated SPN activity and support strategies to reduce striatal glutamate signaling for PD therapy.

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“…2 of Delis et al, 2013) possibly being one cause of LID (Cenci & Konradi, 2010), effects of DA agonism on DA-deficient SPN spiking during such behavior is poorly researched. Such recordings are rare in primates (not one according to the following review: Boraud et al, 2002, at least one thereafter: Liang et al, 2008, Singh et al, 2015, 2016 and rare and conflicting in rodents (Iversen, 2010, pg. 438;Kish et al, 1999;Chen et al, 2001).…”

Section: Spn Neurophysiology In Da Denervated Conditionsmentioning

confidence: 99%

Pitx3Null Mutant (Striatal Dopamine-Deficient) Mice Have Exaggerated Spiny Projection Neuron Responses to l-DOPA and D1 Agonism and Lack Baseline Striatonigral Spiking

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Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates

Abstract: Singh A, Liang L, Kaneoke Y, Cao X, Papa SM. Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates.

Cited by 49 publications

References 69 publications

Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson’s disease

Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson’s disease

Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates

Pitx3Null Mutant (Striatal Dopamine-Deficient) Mice Have Exaggerated Spiny Projection Neuron Responses to l-DOPA and D1 Agonism and Lack Baseline Striatonigral Spiking

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