Abstract
Dendritic regression of striatal spiny projection neurons (SPNs) is a pathological hallmark of Parkinson’s disease (PD). Here we investigate how chronic dopamine denervation and dopamine replacement with L-DOPA affect the morphology and physiology of direct pathway SPNs (dSPNS) in the rat striatum. We used a lentiviral vector optimized for retrograde labeling (FuG-B-GFP) to identify dSPNs in rats with 6-hydroxydopamine (6-OHDA) lesions. Changes in morphology and physiology of dSPNs were assessed through a combination of patch-clamp recordings and two photon microscopy. The 6-OHDA lesion caused a significant reduction in dSPN dendritic complexity. Following chronic L-DOPA treatment, dSPNs segregated into two equal-sized clusters. One group (here called “cluster-1”), showed sustained dendritic atrophy and a partially normalized electrophysiological phenotype. The other one (“cluster-2”) exhibited dendritic regrowth and a strong reduction of intrinsic excitability. Interestingly, FosB/∆FosB induction by L-DOPA treatment occurred preferentially in cluster-2 dSPNs. Our study demonstrates the feasibility of retrograde FuG-B-GFP labeling to study dSPNs in the rat and reveals, for the first time, that a subgroup of dSPNs shows dendritic sprouting in response to chronic L-DOPA treatment. Investigating the mechanisms and significance of this response will greatly improve our understanding of the adaptations induced by dopamine replacement therapy in PD.
Highlights
Spiny projection neurons (SPNs) are classically divided into two major subpopulations based on anatomical and functional properties[1,2,3]
Human post-mortem studies of the striatum in Parkinson’s disease (PD) reported severe shrinkage of spiny projection neurons (SPNs) dendrites[10,11,12]. They could not specify whether both SPN populations were affected, nor whether the dendritic atrophy was caused by the primary disease or by DA replacement therapy, which leads to the development of L-DOPA-induced dyskinesia (LID) in the majority of PD patients
FuG-B-GFP labels striatonigral neurons with a ‘classical’ direct-pathway SPNs (dSPNs) phenotype, we injected the same construct into the substantia nigra pars reticulata (SNr) of transgenic mice that express a red fluorophore under the dopamine D1-receptor promoter (BACdrd1a-tdTomato mice)
Summary
Spiny projection neurons (SPNs) are classically divided into two major subpopulations based on anatomical and functional properties[1,2,3]. Human post-mortem studies of the striatum in Parkinson’s disease (PD) reported severe shrinkage of SPN dendrites[10,11,12] They could not specify whether both SPN populations were affected, nor whether the dendritic atrophy was caused by the primary disease or by DA replacement therapy, which leads to the development of L-DOPA-induced dyskinesia (LID) in the majority of PD patients. We set out to examine the morphological-physiological properties of identified dSPNs in a chronic rodent model of PD exposed to prolonged L-DOPA treatment. To this end, we chose to use rats instead of mice because rats exhibit a stable behavioral and molecular phenotype over many months after complete nigrostriatal lesions (reviewed in[16]). Our data further suggest that the dendritic sprouting of some SPNs during chronic L-DOPA treatment may depend on a high expression of ∆FosB
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