| More than 40% of the Parkinson`s disease (PD) patients develop levodopa-induced dyskinesias (LIDs) after 4-6 years of levodopa (L-dopa) treatment, makes LIDs the most common and disabling side-effects. The clinical manifestations include dystonia and hyperkinesias, all termed abnormal involuntary movements (AIMs). With limited knowledge of the mechanisms underlying LIDs, the long-term clinical efficacy of L-dopa in treating PD has been questioned.;In the first part of the study, we characterized a rat model of LIDs. While the nonhuman primates are the best candidate as the animal model of LIDs, the rodents, especially the rats, serve as a more economical and convenient alternative. In this study, we used a 6-hydroxydopamine (6-OHDA) rat model to create a parkinsonian state, followed by a three-week L-dopa treatment. Our results replicate previous findings and further demonstrated that the complete lesion (dopamine loss > 90%) is necessary but not sufficient to induce the dyskinetic behaviors.;In the second part of the study, we examined the structural plasticity of excitatory synapses from corticostriatal and thalamostriatal pathways in the rat model of LIDs to investigate the adaptation of these striatal circuits during dyskinesias. Numerous studies have implicated enhanced glutamate signaling and persistent long-term potentiation (LTP) as central to the behavioral sensitization phenomenon of LIDs. Moreover, experience-dependent alterations in behavior are thought to involve structural modifications, specifically alterations in patterns of synaptic connectivity. Thus, we hypothesized that in the striatum of rats with LIDs, one of two major glutamatergic pathways would form new or altered contacts, especially onto the spines of MSNs. We present here detailed electron microscopic analyses that provide new insight into the nature of the structural and synaptic remodeling of striatal medium spiny neurons (MSNs) in response to LIDs. Our data provide compelling evidence for a dramatic rewiring of the striatum of dyskinetic rats and this rewiring involves corticostriatal but not thalamostriatal contacts onto MSNs. There is a dramatic increase in corticostriatal contacts onto spines and dendrites that appear to be directly linked to dyskinetic behaviors, since they were not seen in the striatum of animals that did not develop dyskinesia. There is also an aberrant increase in spines receiving more than one excitatory contact (i.e., multisynaptic spines) in the dyskinetic animals compared with the 6-hydroxydopamine (6-OHDA)-treated and control rats. Such alterations could substantially impair the ability of striatal neurons to gate cortically driven signals and contribute to the loss of bidirectional synaptic plasticity. |
