Contribution of cholinergic interneurons to striatal pathophysiology in Parkinson’s disease

International audienceParkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of nigral dopaminergic neurons innervating the striatum, the main input structure of the basal ganglia. This creates an imbalance between dopaminergic inputs and cholinergic interneurons (ChIs) within the striatum. The efficacy of anticholinergic drugs, one of the earliest therapy for PD before the discovery of L-3,4-dihydroxyphenylalanine (L-DOPA) suggests an increased cholinergic tone in this disease. The dopamine (DA)-acetylcholine (ACh) balance hypothesis is now revisited with the use of novel cutting-edge techniques (optogenetics, pharmacogenetics, new electrophysiological recordings). This review will provide the background of the specific contribution of ChIs to striatal microcircuit organization in physiological and pathological conditions. The second goal of this review is to delve into the respective contributions of nicotinic and muscarinic receptor cholinergic subunits to the control of striatal afferent and efferent neuronal systems. Special attention will be given to the role played by muscarinic acetylcholine receptors (mAChRs) in the regulation of striatal network which may have important implications in the development of novel therapeutic strategies for motor and cognitive impairment in PD.Total number of pages (41), figure (1) Total number of words: manuscript (5883), abstract (177

Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences

International audienceParkinson's disease (PD) is a progressive neurodegenerative disease originating from the loss of dopa-mine (DA) neurons in the substantia nigra pars compacta (SNC). The small-conductance calcium-activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task. We used a rat model of early PD in which the progressive nigrostriatal DA degeneration was produced by bilateral infusions of 6-hydroxydopamine (6-OHDA) into the striatum. In situ hybridization of SK2 and SK3 mRNA and binding of iodinated apamin (SK2/SK3 blocker) were performed at 1, 8 or 21 days postsurgery in sham and 6-OHDA lesion groups. A significant decrease of SK3 channel expression was found in the SNC of lesioned animals at the three time points, with no change of SK2 channel expression. Interestingly, an upregulation of SK2 mRNA and apamin binding was found in the subthalamic nucleus (STN) at 21 days postlesion. These results were confirmed using quantitative real time polymerase chain reaction (qRT-PCR) approach. Functionally, the local infusion of apamin into the STN of parkinsonian rats enhanced the akinetic deficits produced by nigrostriatal DA lesions in a reaction time task while apamin infusion into the SNC had an opposite effect. These effects disappear when the positive modulator of SK channels (CyPPA) is co-administered with apamin. These findings suggest that an upregulation of SK2 channels in the STN may underlie the physiological adjustment to increased subthalamic excitability following partial DA denervation

Targeting metabotropic glutamate receptors (mGluRs) in Parkinson's disease

International audienceThe interplay between dopamine and glutamate in the basal ganglia regulate critical aspects of motor and cognitive behavior. Metabotropic glutamate (mGlu) receptors are key modulators of glutamatergic dysfunction in Parkinson's disease (PD). Preclinical evidence demonstrate that group I mGlu receptor antagonism and groups II and III mGlu receptor activation improve motor symptomatology of PD and decrease l-DOPA-induced dyskinesia by regulating excitatory and inhibitory transmission in the basal ganglia. Emotional and cognitive deficits are also observed in PD. Treatment of these symptoms is challenging and underscore the need for novel effective and well tolerated pharmacological treatments. This article will thus review the currently available knowledge regarding the therapeutic potential of targeting mGlu receptors to restore motor and nonmotor symptoms of PD

Metabotropic glutamate receptors and Parkinson's disease

6th International mGluR Meeting, Taormina, ITALY, SEP 14-19, 2008International audienceno abstrac

Interaction between adenosine and metabotropic glutamate receptors as promising anti-parkinsonian strategy

10th Biennial Meeting of the European-Behavioural-Pharmacology-Society, ANTWERP, BELGIUM, SEP 06-09, 2003International audienceno abstrac

Rôle des récepteurs métabotropiques du glutamate du groupe III dans la maladie de Parkinson

La maladie de Parkinson (MP) résulte de la dégénérescence progressive des neurones dopaminergiques de la substance noire pars compacta qui innervent les ganglions de la base (GB), ensemble de structures souscorticales impliquées dans le contrôle moteur. Au cours de la MP, la perte des neurones dopaminergiques nigrostriés est associée à une hyperactivité réactionnelle des systèmes glutamatergiques au sein des GB. Cette observation a conduit à étudier des stratégies thérapeutiques alternatives au traitement classique à la L-DOPA, visant à réguler l action du glutamate au sein des GB. Les récepteurs métabotropiques du glutamate (mGluRs) appartenant au groupe III (sous-types mGlu4, mGlu6, mGlu7 et mGlu8) sont responsables d effets inhibiteurs présynaptiques à la fois sur la transmission glutamatergique et GABAergique, mais leur implication fonctionnelle dans la régulation de l activité des GB est encore peu connue. Nous avons donc étudié les effets comportementaux d injections locales d agonistes des récepteurs du groupe III, dans différentes structures des GB, sur les déficits induits par des lésions bilatérales des neurones dopaminergiques nigrostriés chez le rat. Afin de mesurer les déficits moteurs (relatifs à l initiation du mouvement ou akinésie) et cognitifs (relatifs aux processus de préparation motrice) produits par les lésions dopaminergiques, nous avons utilisé une tâche conditionnée de temps de réaction simple, développée chez l homme et adaptée aux rongeurs. Nos résultats montrent que l activation préférentielle des mGlu4 dans le globus pallidus (GP), mais pas des autres sous-types de récepteurs, annule les déficits moteurs induits par la lésion des neurones dopaminergiques. Au contraire, l activation des mGlu4/mGlu8 dans la substance noire pars réticulata (SNr) les aggrave et induit une akinésie chez les animaux témoins. Le blocage des récepteurs GABA-A dans ces deux structures produit des effets similaires suggérant une action préférentielle des agonistes mGlu4 sur la transmission GABAergique. Dans la seconde partie de ce travail, nous avons montré que l administration chronique, par voie systémique, d un agoniste non-sélectif des 4 soustypes de récepteurs, l ACPT-I, réduit l akinésie induite par la déplétion dopaminergique. Il induit, par ailleurs, une akinésie chez les animaux témoins. L analyse des effets cellulaires induits par ce traitement révèle que ce composé réduit l hyperactivité métabolique neuronale, observée dans le noyau sous-thalamique et la SNr après lésion dopaminergique. Au contraire, chez les animaux témoins, l ACPT-I induit une augmentation d activité métabolique au niveau de la SNr, suggérant que le niveau d activité dopaminergique est déterminant dans les effets induits par l activation des mGluRs du groupe III. Enfin, dans une dernière partie de ce travail, nous avons étudié l interaction fonctionnelle entre les récepteurs mGlu et les récepteurs A2A de l adénosine. En effet, le blocage pharmacologique des récepteurs A2A réduit les déficits moteurs observés dans différents modèles de la MP. Nos résultats montrent que la co-administration aiguë et chronique de doses sous-liminaires d ACPT-I et de différents antagonistes des récepteurs A2A, réduit l état cataleptique induit par l halopéridol, antagoniste des récepteurs dopaminergiques. L ensemble de ces résultats met donc en évidence l implication des mGluRs du groupe III dans la régulation des processus moteurs impliquant les GB, et suggèrent que leurs interactions multiples avec d autres systèmes conditionnent leur fonction.Parkinson s disease (PD) results from the progressive loss of dopaminergic neurons in the substantia nigra pars compacta that innervate the basal ganglia (BG), a set of subcortical nuclei involved in motor control. In PD, the loss of nigrostriatal dopaminergic neurons is associated with glutamatergic overactivity in the BG. This led to propose therapeutic strategies alternative to L-DOPA treatment, that regulate glutamate action within the BG. Metabotropic glutamate receptors (mGluRs) belonging to group III (mGlu4, mGlu6, mGlu7 et mGlu8) exert presynaptic inhibitory effects on glutamatergic and GABAergic neurotransmission, but the functional involvement of these receptors in regulating BG function is not well defined. We thus have studied the behavioural effects produced by group III receptors agonists, injected in various structures of the BG, to counteract the motor deficits induced by bilateral lesions of dopaminergic nigrostriatal neurons in rats. The motor (related to movement initiation or akinesia) and cognitive deficits (related to motor preparatory processes) induced by dopaminergic lesions were measured in a simple reaction time task developed for rodents and is similar to human tasks. Results show that preferential activation of mGlu4 into the globus pallidus, but not the other group III mGuRs subtypes, reverses the lesion-induced motor deficits. In contrast, activation of mGlu4/8 into the substantia nigra pars reticulata (SNr) enhances lesion-induced motor deficits and produces akinesia in control animals. Moreover, pharmacological blockade of GABA-A receptors into both structures produced similar effects than those observed after group III mGluRs activation, suggesting that a preferential action of these mGlu receptor ligands on GABAergic neurotransmission. In a second part of this work, we show that systemic chronic, but not acute, treatment with a non-subtype selective agonist of group III receptors, ACPT-I, alleviates motor deficits induced by dopaminergic lesions, and produces akinesia in control animals. Analysis of the cellular effects produced by this treatment show that ACPT-I reduces lesion-induced neuronal metabolic hyperactivity in the subthalamic nucleus and SNr. In contrast, in control animals, the same treatment increases metabolic activity in the SNr, thus suggesting that dopaminergic activity triggers group III mGluRs-induced effects. In the last part of this work, we have evaluated the functional interactions between these mGlu and adenosine A2A receptors. Indeed, pharmacological blockade of A2A receptors reduces motor deficits in various PD models. Results show that acute and chronic co-treatment with sub-threshold doses of ACPT-I and various A2A receptor antagonists counteract the cataleptic state induced by the dopaminergic receptor antagonist haloperidol. Altogether, these results demonstrate the involvement of group III mGluRs in regulating motor processes in BG, and suggest that these receptors interact with multiple systems that control their function.AIX-MARSEILLE1-BU Sci.St Charles (130552104) / SudocSudocFranceF