scholarly journals The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2265
Author(s):  
Feras Altwal ◽  
Connor Moon ◽  
Anthony R. West ◽  
Heinz Steiner
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Gene Regulation ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Partial Agonist ◽  
Projection Neurons ◽  
Dopamine Depletion ◽  
Indirect Pathway ◽  
Direct Pathway

Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.

scholarly journals Dopamine modulates the size of striatal projection neuron ensembles

2019 ◽  
Author(s):  
Marta Maltese ◽  
Jeffrey R. March ◽  
Alexander G. Bashaw ◽  
Nicolas X. Tritsch
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Voluntary Movements ◽  
Indirect Pathway ◽  
Two Photon ◽  
Direct Pathway ◽  
Brain Circuits

SUMMARYDopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca2+ imaging to simultaneously monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that, contrary to prevailing models, DA does not modulate activity rates in either pathway strongly or differentially. Instead, DA exerts a prominent influence on the overall number of direct and indirect pathway SPNs recruited during behavior. Chronic loss of midbrain DA neurons in a model of Parkinson’s disease selectively impacts direct pathway ensembles and profoundly alters how they respond to DA elevation. Our results indicate that DA regulates striatal output by dynamically reconfiguring its sparse ensemble code and provide novel insights into the pathophysiology of Parkinson’s disease.

scholarly journals Parallel Movement-suppressing Striatal Output Pathways

2020 ◽  
Author(s):  
Qiaoling Cui ◽  
Xixun Du ◽  
Isaac Y. M. Chang ◽  
Arin Pamukcu ◽  
Varoth Lilascharoen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Body Movement ◽  
Disease Model ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Direct Pathway ◽  
Striatal Projection Neurons ◽  
6 Hydroxydopamine

AbstractThe classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

scholarly journals Inflammatory Animal Model for Parkinson's Disease: The Intranigral Injection of LPS Induced the Inflammatory Process along with the Selective Degeneration of Nigrostriatal Dopaminergic Neurons

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
A. Machado ◽  
A. J. Herrera ◽  
J. L. Venero ◽  
M. Santiago ◽  
R. M. de Pablos ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Dopaminergic Neurons ◽  
Inflammatory Process ◽  
Dopaminergic System ◽  
Neuronal System ◽  
Dopamine Depletion ◽  
Anti Inflammatory ◽  
Dopaminergic Degeneration

We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinson's disease (PD). The implication of neuroinflammation on this disease was originally established in 1988, when the presence of activated microglia in the substantia nigra (SN) of parkinsonians was reported by McGeer et al. Neuroinflammation could be involved in the progression of the disease or even has more direct implications. We injected 2 μg of the potent proinflammatory compound lipopolysaccharide (LPS) in different areas of the CNS, finding that SN displayed the highest inflammatory response and that dopaminergic (body) neurons showed a special and specific sensitivity to this process with the induction of selective dopaminergic degeneration. Neurodegeneration is induced by inflammation since it is prevented by anti-inflammatory compounds. The special sensitivity of dopaminergic neurons seems to be related to the endogenous dopaminergic content, since it is overcome by dopamine depletion. Compounds that activate microglia or induce inflammation have similar effects to LPS. This model suggest that inflammation is an important component of the degeneration of the nigrostriatal dopaminergic system, probably also in PD. Anti-inflammatory treatments could be useful to prevent or slow down the rate of dopaminergic degeneration in this disease.

scholarly journals Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Marta Maltese ◽  
Jeffrey R March ◽  
Alexander G Bashaw ◽  
Nicolas X Tritsch
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Population Level ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Voluntary Movements ◽  
Indirect Pathway ◽  
Two Photon ◽  
Brain Circuits

Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca2+ imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity towards the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson's disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson's disease.

scholarly journals Diverse Short-Term Dynamics of Inhibitory Synapses Converging on Striatal Projection Neurons: Differential Changes in a Rodent Model of Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Janet Barroso-Flores ◽  
Marco A. Herrera-Valdez ◽  
Violeta Gisselle Lopez-Huerta ◽  
Elvira Galarraga ◽  
José Bargas
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Voltage ◽  
Rodent Model ◽  
Inhibitory Synapses ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Dopamine Depletion ◽  
Short Term ◽  
6 Hydroxydopamine

Most neurons in the striatum are projection neurons (SPNs) which make synapses with each other within distances of approximately 100 µm. About 5% of striatal neurons are GABAergic interneurons whose axons expand hundreds of microns. Short-term synaptic plasticity (STSP) between fast-spiking (FS) interneurons and SPNs and between SPNs has been described with electrophysiological and optogenetic techniques. It is difficult to obtain pair recordings from some classes of interneurons and due to limitations of actual techniques, no other types of STSP have been described on SPNs. Diverse STSPs may reflect differences in presynaptic release machineries. Therefore, we focused the present work on answering two questions: Are there different identifiable classes of STSP between GABAergic synapses on SPNs? And, if so, are synapses exhibiting different classes of STSP differentially affected by dopamine depletion? Whole-cell voltage-clamp recordings on SPNs revealed three classes of STSPs: depressing, facilitating, and biphasic (facilitating-depressing), in response to stimulation trains at 20 Hz, in a constant ionic environment. We then used the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson’s disease to show that synapses with different STSPs are differentially affected by dopamine depletion. We propose a general model of STSP that fits all the dynamics found in our recordings.

scholarly journals Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Pérez-Santamarina ◽  
Pedro García-Ruiz ◽  
Dolores Martínez-Rubio ◽  
Mario Ezquerra ◽  
Irene Pla-Navarro ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Regulation ◽  
Rare Variants ◽  
Dopamine Depletion ◽  
Single Nucleotide Variants ◽  
Regulatory Regions ◽  
Functional Variants ◽  
Clinical Series

AbstractParkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD. We found in 10 out of 535 PD patients 6 ANKK1 heterozygous rare alleles located at the 5′UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6 ANKK1 single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro. ANKK1 variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of ATP7B gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the ANKK1 enhancer and PD in two independent clinical series (P = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the ANKK1 locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.

scholarly journals Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

2019 ◽  
Author(s):  
Magdalena K. Baaske ◽  
Eszter Kormann ◽  
Abbey B. Holt ◽  
Alessandro Gulberti ◽  
Colin G. McNamara ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Subthalamic Nucleus ◽  
Full Range ◽  
Spike Timing ◽  
Cortical Stimulation ◽  
Dopamine Depletion ◽  
Indirect Pathway ◽  
Cortical Input ◽  
Beta Frequency

AbstractAbnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson’s disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopamine-depleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

scholarly journals Do human recordings reveal drastic modulations in the discharge of striatal projection neurons in Parkinson’s disease?

2020 ◽  
Author(s):  
Dan Valsky ◽  
Zvi Israel ◽  
Thomas Boraud ◽  
Hagai Bergman ◽  
Marc Deffains
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Neuronal Activity ◽  
Discharge Rate ◽  
Projection Neurons ◽  
Dopamine Depletion ◽  
Striatal Projection Neurons ◽  
Deep Brain

AbstractDopamine depletion of the striatum plays a key role in the pathophysiology of Parkinson’s disease (PD), but our understanding of the changes in the discharge rate and pattern of the striatal projection neurons (SPNs) remains limited. Here, we recorded multi-unit signals from the striatum of PD (N = 934) and dystonic (N = 718) patients undergoing deep brain stimulation surgeries. Using an innovative automated data-driven approach to classify striatal units, we showed that the SPN discharge rate is inversely proportional to the isolation quality and stationarity of the SPNs. In contrast to earlier studies in both PD patients and the non-human primate model of PD, we found no drastic changes in the spiking activity (discharge rate and pattern) of the well-isolated and stationary SPNs of PD patients compared to either dystonic patients or the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations. There was therefore no specific SPN subpopulation (D1 or D2 SPNs) strongly affected by the pathological state. Instead, our results suggest that moderate changes in SPN discharge are most likely amplified by basal ganglia downstream structures, thus leading to the clinical (motor and non-motor) symptoms of PD.Significance statementIn Parkinson’s disease (PD), the loss of the midbrain dopaminergic neurons leads to massive striatal dopamine depletion that provokes abnormal activity throughout the basal ganglia. However, the impact of dopamine depletion on neuronal activity in the striatum is still highly debated. We recorded and examined the neuronal activity in striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. We found that striatal activity was not drastically higher in PD patients compared to either dystonic patients or the normal levels of striatal activity reported in animal studies. In PD, moderate changes in striatal basal activity are therefore most likely amplified by basal ganglia downstream structures.

scholarly journals Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5790
Author(s):  
Feras Altwal ◽  
Fernando E. Padovan-Neto ◽  
Alexandra Ritger ◽  
Heinz Steiner ◽  
Anthony R. West
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Partial Agonist ◽  
Critical Role ◽  
Medium Spiny Neurons ◽  
Cortical Input ◽  
Spiny Neurons ◽  
Underlying Mechanisms

L-DOPA therapy in Parkinson’s disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.

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