D2 dopamine receptors and the striatopallidal pathway modulate L-DOPA-induced dyskinesia in the mouse.

L-DOPA-induced dyskinesia (LID) remains a major complication of Parkinson's disease management for which better therapies are necessary. The contribution of the striatonigral direct pathway to LID is widely acknowledged but whether the striatopallidal pathway is involved remains debated. Selective optogenetic stimulation of striatonigral axon terminals induces dyskinesia in mice rendered hemiparkinsonian with the toxin 6-hydroxydopamine (6-OHDA).

Multicentre observational study on multisystem inflammatory syndrome related to COVID-19 in Argentina.

Background: The impact of the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in low- and middle-income countries remains poorly understood. Our aim was to understand the characteristics and outcomes of PIMS-TS in Argentina.

Methods: This observational, prospective, and retrospective multicenter study enrolled patients younger than 18 years-old manifesting PIMS-TS, Kawasaki disease (KD) or Kawasaki shock syndrome (KSS) between March 2020 and May 2021.

Dorsal striatum coding for the timely execution of action sequences.

The automatic initiation of actions can be highly functional. But occasionally these actions cannot be withheld and are released at inappropriate times, impulsively. Striatal activity has been shown to participate in the timing of action sequence initiation and it has been linked to impulsivity.

D1/D5 Inverse Agonists Restore Striatal Cholinergic Interneuron Physiology in Dyskinetic Mice.

Background: In advanced stages of Parkinson's disease (PD), dyskinesia and motor fluctuations become seriously debilitating and therapeutic options become scarce. Aberrant activity of striatal cholinergic interneurons (SCIN) has been shown to be critical to PD and dyskinesia, but the systemic administration of cholinergic medications can exacerbate extrastriatal-related symptoms. Thus, targeting the mechanisms causing pathological SCIN activity in severe PD with motor fluctuations and dyskinesia is a promising therapeutic alternative.

A familiar study on self-limited childhood epilepsy patients using hIPSC-derived neurons shows a bias towards immaturity at the morphological, electrophysiological and gene expression levels.

Background: Self-limited Childhood Epilepsies are the most prevalent epileptic syndrome in children. Its pathogenesis is unknown. In this disease, symptoms resolve spontaneously in approximately 50% of patients when maturity is reached, prompting to a maturation problem.

Mechanisms of Antiparkinsonian Anticholinergic Therapy Revisited.

Before the advent of L-DOPA, the gold standard symptomatic therapy for Parkinson's disease (PD), anticholinergic drugs (muscarinic receptor antagonists) were the preferred antiparkinsonian therapy, but their unwanted side effects associated with impaired extrastriatal cholinergic function limited their clinical utility. Since most patients treated with L-DOPA also develop unwanted side effects such as L-DOPA-induced dyskinesia (LID), better therapies are needed. Recent studies in animal models demonstrate that optogenetic and chemogenetic manipulation of striatal cholinergic interneurons (SCIN), the main source of striatal acetylcholine, modulate parkinsonism and LID, suggesting that restoring SCIN function might serve as a therapeutic option that avoids extrastriatal anticholinergics' side effects.

Levodopa Causes Striatal Cholinergic Interneuron Burst-Pause Activity in Parkinsonian Mice.

Background: Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa-induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal-related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative.

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

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.

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L-DOPA in a mouse model of Parkinson's disease.

Background And Purpose: L-DOPA-induced dyskinesia (LID) remains a major complication of L-DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L-DOPA.

Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac.

Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs.

Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism.

The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.

Refinement of neuronal synchronization with gamma oscillations in the medial prefrontal cortex after adolescence.

The marked anatomical and functional changes taking place in the medial prefrontal cortex (PFC) during adolescence set grounds for the high incidence of neuropsychiatric disorders with adolescent onset. Although circuit refinement through synapse pruning may constitute the anatomical basis for the cognitive differences reported between adolescents and adults, a physiological correlate of circuit refinement at the level of neuronal ensembles has not been demonstrated. We have recorded neuronal activity together with local field potentials in the medial PFC of juvenile and adult mice under anesthesia, which allowed studying local functional connectivity without behavioral or sensorial interference.

Origin and properties of striatal local field potential responses to cortical stimulation: temporal regulation by fast inhibitory connections.

Evoked striatal field potentials are seldom used to study corticostriatal communication in vivo because little is known about their origin and significance. Here we show that striatal field responses evoked by stimulating the prelimbic cortex in mice are reduced by more than 90% after infusing the AMPA receptor antagonist CNQX close to the recording electrode. Moreover, the amplitude of local field responses and dPSPs recorded in striatal medium spiny neurons increase in parallel with increasing stimulating current intensity.

Striatal Signaling in L-DOPA-Induced Dyskinesia: Common Mechanisms with Drug Abuse and Long Term Memory Involving D1 Dopamine Receptor Stimulation.

Parkinson's disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum. Despite extensive investigation aimed at finding new therapeutic approaches, the dopamine precursor molecule, 3,4-dihydroxyphenyl-l-alanine (l-DOPA), remains the most effective and commonly used treatment. However, chronic treatment and disease progression lead to changes in the brain's response to l-DOPA, resulting in decreased therapeutic effect and the appearance of dyskinesias.

Striatal gating through up states and oscillations in the basal ganglia: Implications for Parkinson's disease.

Up states are a hallmark of striatal physiology. Spontaneous activity in the thalamo-cortical network drives robust plateau depolarizations in the medium spiny projection neurons of the striatum. Medium spiny neuron firing is only possible during up states and is very tightly regulated by dopamine and NMDA receptors.

Reduction of an afterhyperpolarization current increases excitability in striatal cholinergic interneurons in rat parkinsonism.

Striatal cholinergic interneurons show tonic spiking activity in the intact and sliced brain, which stems from intrinsic mechanisms. Because of it, they are also known as "tonically active neurons" (TANs). Another hallmark of TAN electrophysiology is a pause response to appetitive and aversive events and to environmental cues that have predicted these events during learning.

Mapping the effects of three dopamine agonists with different dyskinetogenic potential and receptor selectivity using pharmacological functional magnetic resonance imaging.

The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions.

Effect of chronic treatment with riluzole on the nigrostriatal dopaminergic system in weaver mutant mice.

The effects of a chronic treatment with the anti-glutamate and sodium channel modulating neuroprotective agent riluzole on the degeneration of dopamine-containing neurons were studied in the brain of weaver mutant mice. In these animals, as in Parkinson's disease, dopaminergic neurons of the nigro-striatal pathway undergo spontaneous and progressive cell death. Homozygous weaver mice were orally treated twice a day with either 8 mg/kg riluzole or placebo for 2 months.