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

Cells, vol. 9, pp. 2441

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.

Authors 3

1. Victoria Sofie Witzig Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, RWTH Aachen University, 52074 Aachen, Germany

2. Daniel Komnig Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, RWTH Aachen University, 52074 Aachen, Germany

3. Björn H. Falkenburger corresponding Aachen Department of Neurology JARA-Institute Molecular Neuroscience and Neuroimaging

   RWTH Aachen University · Forschungszentrum Jülich · Technische Universität Dresden · Jülich Aachen Research Alliance · German Center for Neurodegenerative Diseases · German Center for Neurodegenerative Diseases (DZNE) Dresden

   Affiliation as printed

   Department of Neurology, RWTH Aachen University, 52074 Aachen, Germany

   Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany

   Deutsches Zentrum für Neurodegenerative Erkrankungen, 01307 Dresden, Germany

   JARA-Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, 52074 Aachen, Germany