Hyperactive Response of Direct Pathway Striatal Projection Neurons to L-dopa and D1 Agonism in Freely Moving Parkinsonian Mice

Abstract

Dopamine (DA) profoundly stimulates motor function as demonstrated by the hypokinetic motor symptoms in Parkinson's disease (PD) and by the hyperkinetic motor side effects during dopaminergic treatment of PD. Dopamine (DA) receptor-bypassing, optogenetics- and chemogenetics-induced spike firing of striatal DA D1 receptor (D1R)-expressing, direct pathway medium spiny neurons (dSPNs or dMSNs) promotes movements. However, the endogenous D1R-mediated effects, let alone those of DA replacement, on dSPN spike activity in freely-moving animals is not established. Here we show that using transcription factor Pitx3 null mutant (Pitx3Null) mice as a model for severe and consistent DA denervation in the dorsal striatum in Parkinson's disease, antidromically identified striatonigral neurons (D1R-expressing dSPNs) had a lower baseline spike firing rate than that in DA-intact normal mice, and these neurons increased their spike firing more strongly in Pitx3Null mice than in WT mice in response to injection of L-dopa or the D1R agonist, SKF81297; the increase in spike firing temporally coincided with the motor-stimulating effects of L-dopa and SKF81297. Taken together, these results provide the first evidence from freely moving animals that in parkinsonian striatum, identified behavior-promoting dSPNs become hyperactive upon the administration of L-dopa or a D1 agonist, likely contributing to the profound dopaminergic motor stimulation in parkinsonian animals and PD patients.

Circuit Mechanisms of Parkinson’s Disease

“…Arky, arkypallidal; proto, prototypical; M1, primary motor cortex. single-unit recordings of optically and antidromically identified iMSNs and dMSNs in freely moving parkinsonian mice similarly show bidirectional changes in firing rate (Ryan et al, 2018;Sagot et al, 2018). Notably, the firing of both iMSNs and dMSNs lost its normal correlation to locomotion, and iMSN firing was specifically enhanced during periods of immobility.…”

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

“…After the administration of L -DOPA, the firing rate of dSPNs in Parkinsonian mice is much higher than that in healthy controls, whereas the firing rate of iSPNs is reduced below the normal range ( Ryan et al, 2018 ). In addition, using Pitx3 null mutant (Pitx3 –/– ) mice, which is an animal model for PD with severe DA denervation, the firing rate of dSPNs is increased in response to L -DOPA or D 1 receptor agonist, SKF81297 ( Sagot et al, 2018 ). A recent study using imaging somatic Ca 2+ dynamics also reveals that during dyskinesia, dSPNs are hyperactive, whereas iSPNs are hypoactive ( Parker et al, 2018 ).…”

Effects of L-DOPA on Gene Expression in the Frontal Cortex of Rats with Unilateral Lesions of Midbrain Dopaminergic Neurons

“…Cell-type specificity of gene expression L-DOPA impacts cells of different types and subtypes (Yanovsky et al, 2011;Gantz et al, 2015;Masukawa et al, 2017;Sagot et al, 2018); therefore, we analyzed the differentially expressed genes to assess their expression frequency within particular cell subtypes. We used large-scale single-cell RNA-Seq murine datasets from the Allen Institute for Brain Science to identify cell types with previously confirmed transcription of the differentially expressed genes (Allen Institute for Brain Science, 2015; Tasic et al, 2018).…”