Abnormal hyperactivity of specific striatal ensembles encodes distinct dyskinetic behaviors revealed by high-resolution clustering DOI Creative Commons
Cristina Alcacer, Andreas Klaus, Marcelo Mendonça

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 8, 2024

L-DOPA-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy in Parkinsońs disease and the most common hyperkinetic disorder basal ganglia origin. Abnormal activity striatal D1 D2 spiny projection neurons (SPNs) critical for LID, yet link between SPN patterns specific dyskinetic movements remains unknown. To explore this, we developed novel method clustering based on high-resolution motion sensors video recordings. In mouse model this identified two main types pathological rotations, all absent during normal behavior. Using single-cell resolution imaging, found that sets both D2-SPNs were abnormally active these movements. Under baseline conditions, same behaviors sharing physical features with LID These findings indicate ensembles behavior-encoding D1- form new combinations hyperactive mediating

Language: Английский

State-dependent modulation of spiny projection neurons controls levodopa-induced dyskinesia in a mouse model of Parkinson's disease DOI Creative Commons
Shenyu Zhai, Qiaoling Cui,

David L. Wokosin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

In the later stages of Parkinson's disease (PD), patients often manifest levodopa-induced dyskinesia (LID), compromising their quality life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this gap, intrinsic synaptic changes in striatal spiny projection neurons (SPNs) triggered by sustained elevation dopamine (DA) during were characterized using electrophysiological, pharmacological, molecular behavioral approaches. Our studies revealed that excitability functional corticostriatal connectivity SPNs dyskinetic mice oscillate between on- off-states a cell- state-specific manner. Although levodopa, these rapid oscillations SPN properties depended on both dopaminergic cholinergic signaling. mouse PD model, disrupting M1 muscarinic receptor signaling specifically iSPNs or deleting its downstream partner CalDAG-GEFI blunted oscillation connectivity, enhanced beneficial effects levodopa attenuated severity.

Language: Английский

Citations

0
A positive allosteric modulator of α7 nicotinic receptor reduces levodopa-induced dyskinesias in hemi-parkinsonian mice DOI

Alejandra Gómez-Paz,

Vladimir Calderón,

Aldo Luna-Leal

et al.

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177655 - 177655

Published: April 1, 2025

Language: Английский

Citations

0
Sexual Dimorphism in Levodopa‐Induced Dyskinesia Following Parkinson's Disease: Uncharted Territory DOI Creative Commons
Lily M. Bentall, Louise C. Parr‐Brownlie

European Journal of Neuroscience, Journal Year: 2025, Volume and Issue: 61(9)

Published: May 1, 2025

ABSTRACT Sexual dimorphism is well‐documented in Parkinson's disease (PD); however, when it comes to levodopa‐induced dyskinesia (LID), epidemiological and clinical findings are scarce. This an oversight because recent studies show significant correlations between LID risk female sex. Estrogen strongly impacts neuronal function, affecting cognitive tasks such as movement, object recognition, reward. In movement pathways, estrogen increases dopamine synthesis, transmission, regulation, resulting neuroprotection for PD women. However, following menopause, prevalence, symptom severity, increase Consequently, early mid‐life state neuroprotective, but later life becomes a factor LID. review explores estrogen's action the brain, specifically within system. described prevalence onset of We examine cellular basis role sexual integrate these ideas hypothesize why higher women, than men, with PD. Lastly, this proposes that women need their symptoms be considered managed differently males. Treatment should based on menopausal stage, may masking, exacerbating, or complicating symptoms. Importantly, we present concepts stimulate discussion among bench scientists so key experiments can conducted mechanisms underlying LID, they prevented improve quality men living future.

Language: Английский

Citations

0
Striatal lateral inhibition regulates action selection in a mouse model of levodopa-induced dyskinesia DOI Creative Commons
Emily L Twedell, Chloe J. Bair-Marshall, Allison E. Girasole

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 12, 2024

SUMMARY Striatal medium spiny neurons (MSNs) integrate multiple external inputs to shape motor output. In addition, MSNs form local inhibitory synaptic connections with one another. The function of striatal lateral inhibition is unknown, but possibility in selecting an intended action while suppressing alternatives. Action selection disrupted several movement disorders, including levodopa-induced dyskinesia (LID), a complication Parkinson’s disease (PD) therapy characterized by involuntary movements. Here, we identify chronic changes the strength synapses mouse model PD/LID. These are also modulated acute dopamine signaling. Chemogenetic suppression originating from D2 receptor-expressing lowers threshold develop movements vivo , supporting role control. By examining basal ganglia and dysfunction, expand framework surrounding microcircuitry selection.

Language: Английский

Citations

1
Abnormal hyperactivity of specific striatal ensembles encodes distinct dyskinetic behaviors revealed by high-resolution clustering DOI Creative Commons
Cristina Alcacer, Andreas Klaus, Marcelo Mendonça

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 8, 2024

L-DOPA-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy in Parkinsońs disease and the most common hyperkinetic disorder basal ganglia origin. Abnormal activity striatal D1 D2 spiny projection neurons (SPNs) critical for LID, yet link between SPN patterns specific dyskinetic movements remains unknown. To explore this, we developed novel method clustering based on high-resolution motion sensors video recordings. In mouse model this identified two main types pathological rotations, all absent during normal behavior. Using single-cell resolution imaging, found that sets both D2-SPNs were abnormally active these movements. Under baseline conditions, same behaviors sharing physical features with LID These findings indicate ensembles behavior-encoding D1- form new combinations hyperactive mediating

Language: Английский

Citations

0