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Abstract
Motor and cognitive functions depend on the coordinated interactions between dopamine
(DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was
assumed to accompany DA deficiency based on the outcome of pharmacological treatments
and measurements in animals that were critically depleted of DA. Using Slc6a3 DTR/+
diphtheria toxin sensitive mice, we demonstrate that a progressive and L-dopa-responsive
DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated
cation (HCN) channels that encode the spike-timing of ACh-releasing tonically-active
striatal interneurons (ChIs). Although the production and release of ACh and DA are
reduced, the preponderance of ACh over DA contributes to the motor deficit. The increase
in striatal ACh relative to DA is heightened via D1-type DA receptors that activate
ChIs in response to DA release from residual axons. These results suggest that stabilizing
the expression of HCN channels may improve ACh-DA reciprocity and motor function in
Parkinson’s disease (PD). McKinley et al. use a new model of Parkinson's disease to
show that a reduction in dopamine modifies the availability of acetylcholine within
the striatum, suggesting that treatment of the disease requires restoration of the
balance between these neurotransmitters.