Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible.

Björn H. Falkenburger,Daniel Komnig,Victoria Sofie Witzig

doi:10.3390/cells9112441

Abstract

The classical motor symptoms of Parkinson’s disease (PD) are caused by degeneration of dopaminergic neurons in the substantia nigra, which is followed by secondary dendritic pruning and spine loss at striatal medium spiny neurons (MSN). We hypothesize that these morphological changes at MSN underlie at least in part long-term motor complications in PD patients. In order to define the potential benefits and limitations of dopamine substitution, we tested in a mouse model whether dendritic pruning and spine loss can be reversible when dopaminergic axon terminals regenerate. In order to induce degeneration of nigrostriatal dopaminergic neurons we used the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice; 30 mg/kg MPTP was applied i.p. on five consecutive days. In order to assess the consequences of dopamine depletion, mice were analyzed 21 days after the last injection. In order to test reversibility of MSN changes we exploited the property of this model that striatal axon terminals regenerate by sprouting within 90 days and analyzed a second cohort 90 days after MPTP. Degeneration of dopaminergic neurons was confirmed by counting TH-positive neurons in the substantia nigra and by analyzing striatal catecholamines. Striatal catecholamine recovered 90 days after MPTP. MSN morphology was visualized by Golgi staining and quantified as total dendritic length, number of dendritic branch points, and density of dendritic spines. All morphological parameters of striatal MSN were reduced 21 days after MPTP. Statistical analysis indicated that dendritic pruning and the reduction of spine density represent two distinct responses to dopamine depletion. Ninety days after MPTP, all morphological changes recovered. Our findings demonstrate that morphological changes in striatal MSN resulting from dopamine depletion are reversible. They suggest that under optimal conditions, symptomatic dopaminergic therapy might be able to prevent maladaptive plasticity and long-term motor complications in PD patients.

Highlights

The classic motor symptoms of Parkinson disease (PD) are tremor, rigidity and bradykinesia.They result from the degeneration of dopaminergic neurons in the substantia nigra (SN) and the resulting dopamine deficiency in the striatum
In order to deplete dopaminergic neurons of the SN in mice, we used the subacute regimen of MPTP where mice are injected i.p. with 30 mg/kg of MPTP on five consecutive days (Figure 1A)
In this study we observed morphological alterations in striatal medium spiny neurons (MSN) after MPTP-induced degeneration of dopaminergic neurons that are consistent with findings in PD patients and other animal models

Summary

Introduction

The classic motor symptoms of Parkinson disease (PD) are tremor, rigidity and bradykinesia. They result from the degeneration of dopaminergic neurons in the substantia nigra (SN) and the resulting dopamine deficiency in the striatum. The cardinal PD motor symptoms are alleviated by. Cells 2020, 9, 2441 the dopamine precursor levodopa and by dopamine receptor agonists [1,2]. Motor symptoms remain responsive to these dopaminergic medications throughout the course of PD. In advanced PD, symptom control is hampered by the fact that a single dose of medication triggers dyskinesia more and lasts for a shorter period of time. Presynaptic mechanisms can explain some features of these motor fluctuations but not their induction by dopamine receptor agonists [3,4]

Methods

Results

Conclusion