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The direct and indirect pathways of the basal ganglia have been proposed to oppositely regulate locomotion and differentially contribute to pathological behaviors. Analysis of the distinct contributions of each pathway to behavior has been a challenge, however, due to the difficulty of selectively investigating the neurons comprising the two pathways using conventional techniques. Here we present two mouse models in which the function of striatonigral or striatopallidal neurons is selectively disrupted due to cell typespecific deletion of the striatal signaling protein dopamine-and cAMP-regulated phosphoprotein Mr 32kDa (DARPP-32). Using these mice, we found that the loss of DARPP-32 in striatonigral neurons decreased basal and cocaine-induced locomotion and abolished dyskinetic behaviors in response to the Parkinson's disease drug L-DOPA. Conversely, the loss of DARPP-32 in striatopallidal neurons produced a robust increase in locomotor activity and a strongly reduced cataleptic response to the antipsychotic drug haloperidol. These findings provide insight into the selective contributions of the direct and indirect pathways to striatal motor behaviors.basal ganglia | DARPP-32 | locomotor behavior | striatonigral | striatopallidal T he basal ganglia (BG) are subcortical structures that coordinate vital behaviors including movement, reward, and motivational processes (1). BG dysfunction is associated with several human diseases, including Parkinson's disease (PD), schizophrenia, and drug addiction. The striatum receives the majority of input into the BG, and projects to the output nuclei of the BG via two pathways that work together to modulate behavior: the D1 receptor (D1R)-expressing direct pathway, which projects to the substantia nigra pars reticulata (SNpr), and the D2 receptor (D2R)-expressing indirect pathway, which projects to the medial globus pallidus (GP) (2). Classical models of the BG propose that these two efferent pathways exert opposing effects on locomotor behavior (3, 4); namely, activation of the direct pathway increases locomotor activity, whereas the indirect pathway exerts a tonic inhibitory tone. Thus, an imbalance of these two pathways would disrupt coordinated movement, resulting in hypokinetic or hyperkinetic movement disorders (3). Direct confirmation of these hypotheses has been hindered by difficulty in selectively targeting direct and indirect pathway neurons with traditional surgical and pharmacological techniques.An understanding of the differential contribution of the direct and indirect pathways to behavior is essential for generating more selective therapies for BG-related disorders. This would be especially valuable in the case of PD and schizophrenia, where motor complications can result from pharmacological treatment. For example, the positive symptoms of schizophrenia are effectively treated with typical antipsychotic drugs, such as haloperidol; however, these drugs are often associated with extrapyramidal side effects including catalepsy, manifested as extreme hypolocomoti...

Parkinson's disease (PD), a disorder caused by degeneration of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by motor side effects, or dyskinesia. We show that administration of l-DOPA in a mouse model of Parkinsonism led to dopamine D1 receptor-mediated activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is implicated in several forms of synaptic plasticity. This response occurred selectively in the GABAergic medium spiny neurons that project directly from the striatum to the output structures of the basal ganglia. The l-DOPA-mediated activation of mTORC1 persisted in mice that developed dyskinesia. Moreover, the mTORC1 inhibitor rapamycin prevented the development of dyskinesia without affecting the therapeutic efficacy of l-DOPA. Thus, the mTORC1 signaling cascade represents a promising target for the design of anti-Parkinsonian therapies.

In the dopamine‐depleted striatum, extracellular signal‐regulated kinase (ERK) signaling is implicated in the development of l‐DOPA‐induced dyskinesia. To gain insights on its role in this disorder, we examined the effects of l‐DOPA on the state of phosphorylation of ERK and downstream target proteins in striatopallidal and striatonigral medium spiny neurons (MSNs). For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D2 receptor (Drd2‐EGFP mice) or the dopamine D1 receptor (Drd1a‐EGFP mice), which are expressed in striatopallidal and striatonigral MSNs, respectively. In 6‐hydroxydopamine‐lesioned Drd2‐EGFP mice, l‐DOPA increased the phosphorylation of ERK, mitogen‐ and stress‐activated kinase 1 and histone H3, selectively in EGFP‐negative MSNs. Conversely, a complete co‐localization between EGFP and these phosphoproteins was observed in Drd1a‐EGFP mice. The effect of l‐DOPA was prevented by blockade of dopamine D1 receptors. The same pattern of activation of ERK signaling was observed in dyskinetic mice, after repeated administration of l‐DOPA. Our results demonstrate that in the dopamine‐depleted striatum, l‐DOPA activates ERK signaling specifically in striatonigral MSNs. This regulation may result in ERK‐dependent changes in striatal plasticity leading to dyskinesia.