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Striatal ERK is Activated in Response to L‐DOPA Administration in a Knock‐in Mouse Model of DOPA‐Responsive Dystonia

Abnormal dopamine (DA) neurotransmission is associated with many dystonic disorders; however, the precise nature of the defects in DA transmission that result in dystonia are not known. To address this question, we used a knock‐in mouse model of L‐DOPA‐responsive dystonia (DRD). DRD mice display the core features of the human disorder, including reduced striatal DA levels and abnormal movement that improves in response to L‐DOPA, the precursor to DA. In the striatum, DA promotes movement by activating D1 receptors (D1Rs) expressed on direct pathway spiny projection neurons (SPNs) and inhibits movement by activating D2 receptors (D2Rs) expressed on indirect pathway SPNs. D1Rs stimulate adenylate cyclase (AC) activity and D2Rs inhibit AC; however, in DRD mice, D1Rs display an exaggerated AC response to D1 agonist stimulation and D2Rs exhibit a change in valence whereby D2R agonists increase AC. Our objective was to determine signaling alterations in both SPN subtypes downstream of AC, specifically phosphorylated ERK (p‐ERK), that contribute to the alleviation of dystonia by L‐DOPA to identify downstream targets that may serve as novel therapeutic targets. DRD and control mice were subcutaneously injected with L‐DOPA (10 mg/kg), the D1R agonist SKF 81297 (0.2 mg/kg), the D2R agonist quinpirole (0.1 mg/kg), or saline. Mice were perfused 45 min after drug treatment and striatal sections were immunostained for p‐ERK. DRD mice showed a significant and robust increase in p‐ERK levels in the dorsal striatum in response to L‐DOPA treatment compared to controls and saline‐treated mice. In contrast, SKF 81297 or quinpirole treatment evoked only modest changes in p‐ERK. The L‐DOPA specific increase in p‐ERK suggests that D1R and D2R co‐activation may regulate p‐ERK and/or that p‐ERK may serve as a coincidence detector for convergent DA and glutamatergic signaling that occurs when endogenous DA signaling is restored in the striatum. Future studies are aimed to elucidate cell‐type specific mechanisms underlying increased p‐ERK in response to L‐DOPA in DRD mice to refine downstream signaling mechanisms that are instrumental to the therapeutic effects.