Selective activation of striatal indirect pathway suppresses levodopa induced-dyskinesias.

Levodopa (L-DOPA) administration remains the gold standard therapy for Parkinson's disease (PD). Despite several pharmacological advances in the use of L-DOPA, a high proportion of chronically treated patients continues to suffer disabling involuntary movements, namely, L-DOPA-induced dyskinesias (LIDs). As part of the effort to stop these unwanted side effects, the present study used a rodent model to identify and manipulate the striatal outflow circuitry responsible for LIDs. To do so, optogenetic technology was used to activate separately the striatal direct (D1R- expressing) and indirect (D2R- expressing) pathways in a mouse model of PD. Firstly, D1-cre or A2a-cre animals received unilateral injections of neurotoxin 6-hydroxydopamine (6-OHDA) to simulate the loss of dopamine observed in PD patients. The effects of independently stimulating each pathway were tested to see if experimental dyskinesias could be induced. Secondly, dopamine depleted A2a-cre animals received systemic L-DOPA to evoke dyskinetic movements. The ability of indirect pathway optogenetic stimulation to suppress pre-established LIDs was then tested. Selective manipulation of direct pathway evoked optodyskinesias both in dopamine depleted and intact animals, but optical inhibition of these neurons failed to suppress LIDs. On the other hand, selective activation of indirect striatal projection neurons produced an immediate and reliable suppression of LIDs. Thus, a functional dissociation has been found here whereby activation of D1R- and D2R-expressing projection neurons evokes and inhibits LIDs respectively, supporting the notion of tight interaction between the two striatal efferent systems in both normal and pathological conditions. This points to the importance of maintaining an equilibrium in the activity of both striatal pathways to produce normal movement. Finally, the ability of selective indirect pathway optogenetic activation to block the expression of LIDs in an animal model of PD sheds light on intrinsic mechanisms responsible for striatal-based dyskinesias and identifies a potential therapeutic target for suppressing LIDs in PD patients.

Shedding light on dyskinesias.

Dopamine replacement therapy with L-DOPA remains the most widely prescribed treatment for Parkinson disease. However, prolonged treatment due to disease progression frequently causes unwanted motor movements known as levodopa-induced dyskinesias. Previous studies have established that alterations to the efferent circuitry of the striatum, a principal component of the basal ganglia, are in part responsible for the pathological motor consequences of prolonged levodopa treatment. While the role of the striatal direct pathway is widely accepted, the engagement of the striatal indirect pathway in dyskinetic pathophysiology is still under consideration. However, recent investigations have finally shown that the activity of both striatal pathways changes as a consequence of dopamine depletion and dyskinetic behavioural conditions. In addition, it has been reported that drug-induced structural alterations to indirect pathway medium spiny neurons, together with associated changes in synaptic plasticity and firing patterns, could contribute importantly to the development of dyskinesia. These findings, together with recent opto- and chemogenetic studies, suggest that a critical imbalance in the activity between both striatal pathways is sufficient to cause dyskinesia in both rodent and primate models of Parkinson disease. In animal models, and in human patients, dyskinetic behaviours elicited by this efferent pathway imbalance can be achieved even in the absence of dopamine denervation. In this review, we summarize recent and past findings to better understand this complex pathology with the aim of pursuing specific cell-type therapies to re-balance efferent striatal activity.

Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease.

BACKGROUND: Long-term levodopa (l-dopa) treatment is associated with the development of l-dopa-induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l-dopa-induced dyskinesias are not well understood. METHODS: We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6-hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno-associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. RESULTS: Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6-hydroxydopamine lesion but l-dopa naïve rats induced involuntary movements similar to l-dopa-induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l-dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l-dopa-induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine-depleted hemisphere. CONCLUSION: Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6-hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato-nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l-dopa-induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society.

Dopamine neuron activity encodes the length of upcoming contralateral movement sequences.

Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson's disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter. However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences. We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.