Transiently-elevated dopamine triggers plasticity that preserves motor function, striatal neuron morphology, and thalamostriatal input in a mouse model of Parkinson's disease

Abstract

Loss of nigrostriatal dopamine (DA) neurons in Parkinson's disease (PD) produces motor symptoms by disrupting the normal circuitry of striatal projection neurons. Here, we report that the Transient Elevation of Dopamine (TED) within a defined window of 6-OHDA-induced DA depletion preserves normal motor behaviorfor months. We also observed a preservation of mature spines specifically on direct pathway striatal projection neurons (dSPNs) and not indirect pathway striatal projection neurons (iSPNs). Preservation of motor behavior and dSPN spines required enhanced activation of striatal D1 receptors. Circuit mapping showed input from primary motor cortex was reduced, while input from parafascicular thalamus was unchanged in both TED mice and controls of both sexes, suggesting rewiring of excitatory inputs to dSPNs from other cortical or thalamic areas in TED mice. Lastly, thalamostriatal paired pulse facilitation, normally depressed following DA depletion, is preserved in TED mice. Although the causal basis of motor preservation remains unresolved, our findings reveal that a schedule of transiently increasing striatal DA surrounding the depletion of dopamine can engage a long-lasting plasticity that markedly delays the onset of motor impairment