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

Ben Sagot,Fu-Ming Zhou,Li Li

doi:10.3389/fncir.2018.00057

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.

Highlights

The motor- and behavior-promoting DA system is highly concentrated in the striatum: the striatum receives an extremely dense DA innervation originated in the midbrain DA areas (Figure 1A), and the main neuronal population in the striatum, the medium spiny neurons (MSNs; referred to as SPNs since they are the projection neurons of the striatum), express extremely high levels of D1 receptor (D1R) in dMSNs and D2Rs in iMSNs (Gerfen and Bolam, 2017; Zhou, 2017), providing an anatomical and molecular substrate for intense DA signaling in the striatum
We focused on the dorsal striatum where DA denervation is severe and DA receptors are hyperfunctional in Pitx3Null mice (Wei et al, 2013, 2017; Ding et al, 2015)
We found that in freely moving Pitx3Null mice with DA denervation-induced DA receptor hyperfunctionality, L-dopa and D1 agonism each triggers hyperactive spike responses in identified striatonigral neurons, and this excitation temporally coincides with the motor stimulation that was characterized in our prior studies (Li and Zhou, 2013; Wang and Zhou, 2017)

Summary

Introduction

The motor- and behavior-promoting DA system is highly concentrated in the striatum: the striatum receives an extremely dense DA innervation originated in the midbrain DA areas (Figure 1A), and the main neuronal population in the striatum, the medium spiny neurons (MSNs; referred to as SPNs since they are the projection neurons of the striatum), express extremely high levels of D1Rs in dMSNs and D2Rs in iMSNs (Gerfen and Bolam, 2017; Zhou, 2017), providing an anatomical and molecular substrate for intense DA signaling in the striatum. Systemic administration of D1R agonists strongly stimulates motor activity in rodent and non-human primate PD models and PD patients (Mailman et al, 2001; Li and Zhou, 2013); important, microinjection of a D1 agonist into the dorsal striatum but not GPe, SNr or the motor cortex induces strong motor activity in parkinsonian animals (Wang and Zhou, 2017). Taken together, these literature data indicate a critical importance of striatal D1Rs– likely those in dSPNs–in dopaminergic motor stimulation in PD

Objectives

Methods

Results

Discussion

Conclusion