The thorny problem of dyskinesias: dendritic spines, synaptic plasticity, and striatal dysfunction.

Abnormal involuntary movements, particularly levodopainduced dyskinesia (LID) and antipsychotic drug-elicited tardive dyskinesia, are among the most difficult to manage adverse effects associated with the treatment of Parkinson’s disease (PD) and schizophrenia, respectively. The mechanisms underlying dyskinesias in levodopa-treated PD have been studied for decades. Over this time, there has been a gradual shift from a focus on mechanisms associated with surviving dopamine (presynaptic) neurons to changes in dopaminoceptive cells in the striatum. The medium spiny neurons (MSNs) of the striatum account for more than 90% of striatal neurons. Medium spiny neurons share a common morphology of medium-sized cell bodies with radially extending dendrites that are richly invested with dendritic spines, the thorny excrescences noted by Santiago Ramon y Cajal in the late 18th century. Displaying his usual brilliant ability to predict functional correlates of his structural observations, Cajal suggested that these spines were the site of interaction between presynaptic axons and their postsynaptic targets, and today it is clear that the dendritic spine is the primary site at which excitatory inputs regulate neurons. There are two major subtypes of MSNs, defined on the basis of the dopamine receptor present on the cell, the peptide co-transmitter in these neurons, and the projection target of the cell: MSNs that express dopamine D1 receptors, preprotachykinin messenger RNA, and project to the pars reticulata of the rodent substantia nigra (direct pathway cells), and D2 receptor-expressing MSNs that contain preproenkephalin and innervate that globus pallidus before routing to the substantia nigra (indirect pathway cells). In this issue, Suárez et al. (1) report that dopamine denervation of the striatum results in a loss of dendritic spines but not dendritic length or cell body size in MSNs, with levodopa treatment reversing the spine loss observed in dopamine-denervated mice. The authors used either D1 receptor td-Tomato or D2 receptorenhanced green fluorescent protein bacterial artificial chromosome (BAC) transgenic mice subjected to unilateral intrastriatal injections of 6-hydoxydopamine or vehicle. Two to three weeks later, the animals were started on 2 weeks of daily levodopa/ benserazide or vehicle injections, resulting in contralateral forelimb and orofacial dyskinesias and trunk dystonia. Suárez et al. (1) used the fluorescent reporters in the two mouse lines to guide intracellular fills of the MSNs with Lucifer Yellow, permitting full structural reconstructions of the cells, as well as the ability to selectively define physiological changes in D1 and D2 MSNs. Suárez et al. (1) found that the overall decrease in MSN spine density was not attributable to a selective loss of spines in one of the two types of MSNs but occurred in both D1and D2-expressing MSNs. Dendritic spine loss was restricted to striatal territories