Veronica Ghiglieri

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.

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.

The distinct role of medium spiny neurons and cholinergic interneurons in the D₂/A₂A receptor interaction in the striatum: implications for Parkinson's disease

A2A adenosine receptor antagonists are currently under investigation as potential therapeutic agents for Parkinsons disease (PD). However, the molecular mechanisms underlying this therapeutic effect is still unclear. A functional antagonism exists between A2A adenosine and D2 dopamine (DA) receptors that are coexpressed in striatal medium spiny neurons (MSNs) of the indirect pathway. Since this interaction could also occur in other neuronal subtypes, we have analyzed the pharmacological modulation of this relationship in murine MSNs of the direct and indirect pathways as well in striatal cholinergic interneurons. Under physiological conditions, endogenous cannabinoids (eCBs) play a major role in the inhibitory effect on striatal glutamatergic transmission exerted by the concomitant activation of D2 DA receptors and blockade of A2A receptors in both D2- and D1-expressing striatal MSNs. In experimental models of PD, the inhibition of striatal glutamatergic activity exerted by D2 receptor activation did not require the concomitant inhibition of A2A receptors, while it was still dependent on the activation of CB1 receptors in both D2- and D1-expressing MSNs. Interestingly, the antagonism of M1 muscarinic receptors blocked the effects of D2/A2A receptor modulation on MSNs. Moreover, in cholinergic interneurons we found coexpression of D2 and A2A receptors and a reduction of the firing frequency exerted by the same pharmacological agents that reduced excitatory transmission in MSNs. This evidence supports the hypothesis that striatal cholinergic interneurons, projecting to virtually all MSN subtypes, are involved in the D2/A2A and endocannabinoid-mediated effects observed on both subpopulations of MSNs in physiological conditions and in experimental PD.

Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia

The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinsons disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.

Distinct Levels of Dopamine Denervation Differentially Alter Striatal Synaptic Plasticity and NMDA Receptor Subunit Composition

A correct interplay between dopamine (DA) and glutamate is essential for corticostriatal synaptic plasticity and motor activity. In an experimental model of Parkinsons disease (PD) obtained in rats, the complete depletion of striatal DA, mimicking advanced stages of the disease, results in the loss of both forms of striatal plasticity: long-term potentiation (LTP) and long-term depression (LTD). However, early PD stages are characterized by an incomplete reduction in striatal DA levels. The mechanism by which this incomplete reduction in DA level affects striatal synaptic plasticity and glutamatergic synapses is unknown. Here we present a model of early PD in which a partial denervation, causing mild motor deficits, selectively affects NMDA-dependent LTP but not LTD and dramatically alters NMDA receptor composition in the postsynaptic density. Our findings show that DA decrease influences corticostriatal synaptic plasticity depending on the level of depletion. The use of the TAT2A cell-permeable peptide, as an innovative therapeutic strategy in early PD, rescues physiological NMDA receptor composition, synaptic plasticity, and motor behavior.

Short-term and long-term plasticity at corticostriatal synapses: Implications for learning and memory

The striatum is the major division of the basal ganglia, representing the input station of the circuit and arguably the principal site within the basal ganglia where information processing occurs. Striatal activity is critically involved in motor control and learning. Many parts of the striatum are involved in reward processing and in various forms of learning and memory, such as reward-association learning. Moreover, the striatum appears to be a brain center for habit formation and is likely to be involved in advanced stages of addiction. The critical role played by the striatum in learning and cognitive processes is thought to be based on changes in neuronal activity when specific behavioral tasks are being learned. Accordingly, excitatory corticostriatal synapses onto both striatal projecting spiny neurons and interneurons are able to undergo the main forms of synaptic plasticity, including long-term potentiation, long-term depression, short-term forms of intrinsic plasticity and spike timing-dependent plasticity. These specific forms of neuroplasticity allow the short-term and long-term selection and differential amplification of cortical neural signals modulating the processes of motor and behavioral selection within the basal ganglia neural circuit.

Molecular mechanisms underlying levodopa-induced dyskinesia.

Although levodopa remains the most effective drug for the symptomatic treatment of Parkinsons disease, chronic therapy with this pharmacological compound initiates a complex cascade of cellular and molecular downstream effects resulting in the development of abnormal involuntary movements. The precise mechanisms underlying the development of levodopa induced dyskinesia, however, are far from being completely elucidated. In the present review, we will describe changes in long‐term synaptic excitability following dopamine (DA) denervation and long‐term levodopa treatment leading to abnormal involuntary movements. In particular, we will address the role of both DA D1 receptors and NMDA glutamate receptors in the induction and maintenance of dyskinesia and abnormal synaptic plasticity. We will also describe the possible interaction between these two receptors in the pathophysiology of dyskinesia taking the advantage of the existing knowledge concerning the mechanisms underlying drug abuse. This latter pathophysiological condition, in fact, seems to share several biochemical transduction pathways with those implicated in levodopa‐induced dyskinesia. Finally, we will briefly discuss the possible implication of A2A adenosine receptors in long‐term motor complications of levodopa therapy and focus on the interaction between A2A and D2 receptors. Future studies are required to understand how the interaction between these various biochemical steps converge to produce a long‐term change in neuronal excitability within the basal ganglia leading to abnormal involuntary movements following levodopa treatment in the DA‐denervated state.

l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation

The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinsons disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor information. Here chronic l-DOPA treatment was administered at two different doses to hemiparkinsonian rats, and electrophysiological recordings were subsequently performed from striatal spiny neurons. Both low and high doses of l-DOPA restored normal LTP, which was disrupted following dopamine (DA) denervation. By the end of the chronic treatment, however, while the low l-DOPA dose induced AIMs only in half of the rats, the high dose caused motor complications in all the treated animals. Interestingly, the dose-related expression of motor complications was associated with a lack of synaptic depotentiation. Our study provides further experimental evidence to support a direct correlation between the daily dosage of l-DOPA and the induction of motor complications and establishes a critical pathophysiological link between the lack of synaptic depotentiation and the expression of AIMs.

Plastic and behavioral abnormalities in experimental Huntington's disease: A crucial role for cholinergic interneurons

Huntingtons disease (HD) is a fatal hereditary neurodegenerative disease causing degeneration of striatal spiny neurons, whereas cholinergic interneurons are spared. This cell-type specific pathology produces an array of abnormalities including involuntary movements, cognitive impairments, and psychiatric disorders. Although the genetic mutation responsible for HD has been identified, little is known about the early synaptic changes occurring within the striatal circuitry at the onset of clinical symptoms. We therefore studied the synaptic plasticity of spiny neurons and cholinergic interneurons in two animal models of early HD. As a pathogenetic model, we used the chronic subcutaneous infusion of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. This treatment caused striatal damage and impaired response flexibility in the cross-maze task as well as defective extinction of conditioned fear suggesting a perseverative behavior. In these animals, we observed a loss of depotentiation in striatal spiny neurons and a lack of long-term potentiation (LTP) in cholinergic interneurons. These abnormalities of striatal synaptic plasticity were also observed in R6/2 transgenic mice, a genetic model of HD, indicating that both genetic and phenotypic models of HD show cell-type specific alterations of LTP. We also found that in control rats, as well as in wild-type (WT) mice, depotentiation of spiny neurons was blocked by either scopolamine or hemicholinium, indicating that reversal of LTP requires activation of muscarinic receptors by endogenous acetylcholine. Our findings suggest that the defective plasticity of cholinergic interneurons could be the primary event mediating abnormal functioning of striatal circuits, and the loss of behavioral flexibility typical of early HD might largely depend on cell-type specific plastic abnormalities.