Direct and indirect pathways in levodopa‐induced dyskinesia: A more complex matter than a network imbalance

In Parkinson’s disease (PD), altered dopamine receptor stimulation exerts its main effects in the striatum producing changes in input integration that lead to imbalance between direct and indirect striatal output pathways and dysfunctional changes in basal ganglia output. The resulting motor symptoms are effectively treated with a replacement therapy using the dopamine precursor L-3,4-dihydroxyphenylalanine (L-dopa). However, with disease progression, pulsatile stimulation of dopamine receptors lead to broader neuronal destabilization and motor complications develop resulting in dyskinesia, a very disabling hyperkinetic long-term side effect of the L-dopa therapy. In the effort to investigate the mechanisms underlying the development of dyskinesia, 20 years ago, a model of basal ganglia network, based on two distinct, direct and indirect, pathways, was proposed. This classic model, conceived independently by R.L. Albin and M.R. DeLong, has stimulated the development of increasingly detailed paradigms that could explain the complexity of roles covered by these subcortical structures. However, in the late 90s, it has become clear that the basal ganglia circuit could no longer be considered as a unidirectional linear system that encodes information exclusively through changes in neuronal firing rate but, rather, as a highly organized network in which changes in neuronal activity could play more prominent roles in motor control. This notion has tremendously advanced our knowledge of basal ganglia function and in the last decade, many important works greatly contributed to the understanding of the pathophysiology of basal ganglia in PD and L-dopa-induced dyskinesia (LID). In particular, efforts to understand how loss of dopamine and subsequent administration of L-dopa lead to motor system dysfunction have increasingly turned toward investigation of whether abnormal dopamine stimulation is associated with changes in striatal synaptic plasticity. In support of this possibility, several studies on experimental models of PD have confirmed the link between nigrostriatal degeneration and loss of the main forms of corticostriatal plasticity. Impairment in the induction of the two forms of striatal synaptic plasticity, the long-term depression (LTD), and the long-term potentiation (LTP) has been found to correlate with dopamine depletion and onset of symptoms in experimental models of PD. Interestingly, while treatment with either high or low doses of L-dopa was able to restore LTP expression in all parkinsonian animals, a different pattern of abnormal plasticity appears in treated animals, depending on the therapeutic outcome of L-dopa treatment. In particular, a form of homeostatic synaptic plasticity, named ‘‘depotentiation,’’ which results from the reversal of established LTP by a lowfrequency stimulation (LFS) protocol, was lost selectively in animals displaying dyskinesia. The expression of an aberrant plasticity in PD and the ability of L-dopa of restoring physiological plasticity selectively Potential conflict of interest: Nothing to report. *Correspondence to: Paolo Calabresi, Clinica Neurologica, Universitá di Perugia, Perugia, Italy. E-mail: calabre@unipg.it Received 9 April 2010; Accepted 15 April 2010 Published online 9 July 2010 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.23244