Barbara Picconi

Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesia

Long-term treatment with the dopamine precursor levodopa (L-DOPA) induces dyskinesia in Parkinsons disease (PD) patients. We divided hemiparkinsonian rats treated chronically with L-DOPA into two groups: one showed motor improvement without dyskinesia, and the other developed debilitating dyskinesias in response to the treatment. We then compared the plasticity of corticostriatal synapses between the two groups. High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in both groups of animals. Control and non-dyskinetic rats showed synaptic depotentiation in response to subsequent low-frequency synaptic stimulation, but dyskinetic rats did not. The depotentiation seen in both L-DOPA–treated non-dyskinetic rats and intact controls was prevented by activation of the D1 subclass of dopamine receptors or inhibition of protein phosphatases. The striata of dyskinetic rats contained abnormally high levels of phospho[Thr34]-DARPP-32, an inhibitor of protein phosphatase 1. These results indicate that abnormal information storage in corticostriatal synapses is linked with the development of L-DOPA–induced dyskinesia.

Dopaminergic control of synaptic plasticity in the dorsal striatum

Cortical glutamatergic and nigral dopaminergic afferents impinge on projection spiny neurons of the striatum, providing the most significant inputs to this structure. Isolated activation of glutamate or dopamine (DA) receptors produces short‐term effects on striatal neurons, whereas the combined stimulation of both glutamate and DA receptors is able to induce long‐lasting modifications of synaptic excitability. Repetitive stimulation of corticostriatal fibres causes a massive release of both glutamate and DA in the striatum and, depending on the glutamate receptor subtype preferentially activated, produces either long‐term depression (LTD) or long‐term potentiation (LTP) of excitatory synaptic transmission. D1‐like and D2‐like DA receptors interact synergistically to allow LTD formation, while they operate in opposition during the induction phase of LTP. Corticostriatal synaptic plasticity is severely impaired after chronic DA denervation and requires the stimulation of DARPP‐32, a small protein expressed in dopaminoceptive spiny neurons which acts as a potent inhibitor of protein phosphatase‐1. In addition, the formation of LTD and LTP requires the activation of PKG and PKA, respectively, in striatal projection neurons. These kinases appear to be stimulated by the activation of D1‐like receptors in distinct neuronal populations.

Experimental Parkinsonism Alters Endocannabinoid Degradation: Implications for Striatal Glutamatergic Transmission

Cannabinoid receptors and their endogenous ligands have been recently identified in the brain as potent inhibitors of neurotransmitter release. Here we show that, in a rat model of Parkinsons disease induced by unilateral nigral lesion with 6-hydroxydopamine (6-OHDA), the striatal levels of anandamide, but not that of the other endocannabinoid 2-arachidonoylglycerol, were increased. Moreover, we observed a decreased activity of the anandamide membrane transporter (AMT) and of the anandamide hydrolase [fatty acid amide hydrolase (FAAH)], whereas the binding of anandamide to cannabinoid receptors was unaffected. Spontaneous glutamatergic activity recorded from striatal spiny neurons was higher in 6-OHDA-lesioned rats. Inhibition of AMT byN-(4-hydroxyphenyl)-arachidonoylamide (AM-404) or by VDM11, or stimulation of the cannabinoid CB1 receptor by HU-210 reduced glutamatergic spontaneous activity in both naı̈ve and 6-OHDA-lesioned animals to a similar extent. Conversely, the FAAH inhibitors phenylmethylsulfonyl fluoride and methyl-arachidonoyl fluorophosphonate were much more effective in 6-OHDA-lesioned animals. The present study shows that inhibition of anandamide hydrolysis might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinsons disease.

Direct and indirect pathways of basal ganglia: a critical reappraisal

The basal ganglia are subcortical nuclei controlling voluntary actions and have been implicated in Parkinsons disease (PD). The prevailing model of basal ganglia function states that two circuits, the direct and indirect pathways, originate from distinct populations of striatal medium spiny neurons (MSNs) and project to different output structures. These circuits are believed to have opposite effects on movement. Specifically, the activity of direct pathway MSNs is postulated to promote movement, whereas the activation of indirect pathway MSNs is hypothesized to inhibit it. Recent findings have revealed that this model might not fully account for the concurrent activation of both pathways during movement. Accordingly, we propose a model in which intrastriatal connections are critical and the two pathways are structurally and functionally intertwined. Thus, all MSNs might either facilitate or inhibit movement depending on the form of synaptic plasticity expressed at a certain moment. In PD, alterations of dopamine-dependent synaptic plasticity could alter this coordinated activity.

A convergent model for cognitive dysfunctions in Parkinson's disease: the critical dopamine–acetylcholine synaptic balance

Parkinsons disease is classically characterised as a motor neurodegenerative disorder. Motor symptoms in the disorder are secondary to an altered dopamine-acetylcholine balance due to reduced striatal dopaminergic tone and subsequent cholinergic overactivity. In the past, anticholinergic drugs were given to improve motor aspects of the disease. There is now an increasing interest in the cognitive and non-motor symptoms of Parkinsons disease and in cholinesterase-inhibitor therapy for dementia associated with Parkinsons disease. In this Personal View, we reconsider the dopamine-acetylcholine balance theory and look at recent clinical findings and the possible cooperative role of dopamine and acetylcholine in the induction and maintenance of the long-lasting changes of striatal and cortical synaptic plasticity. We also discuss a convergent versus parallel model to explain cognitive dysfunctions in Parkinsons disease according to dopamine-acetylcholine dependent alterations in synaptic plasticity.

A model of l-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function ☆

L-DOPA-induced dyskinesia is a major complication of L-DOPA pharmacotherapy in Parkinsons disease, and is thought to depend on abnormal cell signaling in the basal ganglia. In this study, we have addressed the possibility to model L-DOPA-induced dyskinesia in the mouse at both the behavioral and the molecular level. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) either in the medial forebrain bundle (MFB) or in the sensorimotor part of the striatum. Both types of lesion produced a similar degree of forelimb akinesia on the contralateral side of the body. The lowest dose of L-DOPA that could significantly relieve this akinetic deficit (i.e., 6 mg/kg) did not differ between MFB and intrastriatal lesions. The L-DOPA threshold dose for the induction of dyskinesia did however differ between the two lesion types. A daily dose of 6 mg/kg L-DOPA caused MFB lesioned mice to develop abnormal movements affecting orofacial, trunk, and forelimb muscles on the side contralateral to the lesion, whereas a daily dose of 18 mg/kg was required to produce comparable dyskinetic effects in the intrastriatally lesioned animals. The development of abnormal movements was accompanied by a striatal induction of DeltaFosB-like proteins and prodynorphin mRNA, that is, molecular markers that are associated with L-DOPA-induced dyskinesia in both rats and nonhuman primates. We conclude that 6-OHDA lesioned mice exhibit behavioral and cellular features of akinesia and L-DOPA-induced dyskinesia that are similar to those previously characterized in rats. The mouse model of L-DOPA-induced dyskinesia will provide a useful tool to study the molecular determinants of this movement disorder in transgenic mice strains.

Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap

Levodopa is the most effective drug for the treatment of Parkinsons disease. However, the long-term use of this dopamine precursor is complicated by highly disabling fluctuations and dyskinesias. Although preclinical and clinical findings suggest pulsatile stimulation of striatal postsynaptic receptors as a key mechanism underlying levodopa-induced dyskinesias, their pathogenesis is still unclear. In recent years, evidence from animal models of Parkinsons disease has provided important information to understand the effect of specific receptor and post-receptor molecular mechanisms underlying the development of dyskinetic movements. Recent preclinical and clinical data from promising lines of research focus on the differential role of presynaptic versus postsynaptic mechanisms, dopamine receptor subtypes, ionotropic and metabotropic glutamate receptors, and non-dopaminergic neurotransmitter systems in the pathophysiology of levodopa-induced dyskinesias.

A Critical Interaction between NR2B and MAGUK in l-DOPA Induced Dyskinesia

Abnormal function of NMDA receptor has been suggested to be correlated with the pathogenesis of Parkinson’s disease (PD) as well as with the development of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. Here we show that NMDA receptor NR2 subunits display specific alterations of their subcellular distribution in striata from unilateral 6-hydroxydopamine-lesioned, l-DOPA-treated dyskinetic, and l-DOPA-treated nondyskinetic rats. Dyskinetic animals have significantly higher levels of NR2A subunit in the postsynaptic compartment than all other experimental groups, whereas NR2B subunit shows a significant reduction in both dopamine-denervated and dyskinetic rats. These events are paralleled by profound modifications of NMDA receptor NR2B subunit association with interacting elements, i.e., members of the membrane-associated guanylate kinase (MAGUK) protein family postsynaptic density-95, synapse-associated protein-97 and synapse-associated protein-102. Treatment of nondyskinetic animals with a synthetic peptide (TAT2B) able to affect NR2B binding to MAGUK proteins as well as synaptic localization of this subunit in nondyskinetic rats was sufficient to induce a shift of treated rats toward a dyskinetic motor behavior. These data indicate abnormal NR2B redistribution between synaptic and extrasynaptic membranes as an important molecular disturbance of the glutamatergic synapse involved in l-DOPA-induced dyskinesia.

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinsons disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism

Cannabinoid receptors and their endogenous ligands are potent inhibitors of neurotransmitter release in the brain. Here, we show that in a rat model of Parkinsons disease induced by unilateral nigral lesion with 6‐hydroxydopamine (6‐OHDA), the striatal levels of the endocannabinoid anandamide (AEA) were increased, while the activity of its membrane transporter and hydrolase (fatty‐acid amide hydrolase, FAAH) were decreased. These changes were not observed in the cerebellum of the same animals. Moreover, the frequency and amplitude of glutamate‐mediated spontaneous excitatory post‐synaptic currents were augmented in striatal spiny neurones recorded from parkinsonian rats. Remarkably, the anomalies in the endocannabinoid system, as well as those in glutamatergic activity, were completely reversed by chronic treatment of parkinsonian rats with levodopa, and the pharmacological inhibition of FAAH restored a normal glutamatergic activity in 6‐OHDA‐lesioned animals. Thus, the increased striatal levels of AEA may reflect a compensatory mechanism trying to counteract the abnormal corticostriatal glutamatergic drive in parkinsonian rats. However, this mechanism seems to be unsuccessful, since spontaneous excitatory activity is still higher in these animals. Taken together, these data show that anomalies in the endocannabinoid system induced by experimental parkinsonism are restricted to the striatum and can be reversed by chronic levodopa treatment, and suggest that inhibition of FAAH might represent a possible target to decrease the abnormal cortical glutamatergic drive in Parkinsons disease.