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      Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3-/- Mice, a Genetic Model of Parkinson's Disease.

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          Abstract

          In toxin-based models of Parkinson's disease (PD), striatal projection neurons (SPNs) exhibit dendritic atrophy and spine loss concurrent with an increase in excitability. Chronic l-DOPA treatment that induces dyskinesia selectively restores spine density and excitability in indirect pathway SPNs (iSPNs), whereas spine loss and hyperexcitability persist in direct pathway SPNs (dSPNs). These alterations have only been characterized in toxin-based models of PD, raising the possibility that they are an artifact of exposure to the toxin, which may engage compensatory mechanisms independent of the PD-like pathology or due to the loss of dopaminergic afferents. To test all these, we studied the synaptic remodeling in Pitx3-/- or aphakia mice, a genetic model of PD, in which most of the dopamine neurons in the substantia nigra fail to fully differentiate and to innervate the striatum. We made 3D reconstructions of the dendritic arbor and measured excitability in identified SPNs located in dorsal striatum of BAC-Pitx3-/- mice treated with saline or l-DOPA. Both dSPNs and iSPNs from BAC-Pitx3-/- mice had shorter dendritic trees, lower spine density, and more action potentials than their counterparts from WT mice. Chronic l-DOPA treatment restored spine density and firing rate in iSPNs. By contrast, in dSPNs, spine loss and hyperexcitability persisted following l-DOPA treatment, which is similar to what happens in 6-OHDA WT mice. This indicates that dopamine-mediated synaptic remodeling and plasticity is independent of dopamine innervation during SPN development and that Pitx3-/- mice are a good model because they develop the same pathology described in the toxins-based models and in human postmortem studies of advanced PD.SIGNIFICANCE STATEMENT As the only genetic model of Parkinson's disease (PD) that develops dyskinesia, Pitx3-/- mice reproduce the behavioral effects seen in humans and are a good system for studying dopamine-induced synaptic remodeling. The studies we present here establish that the structural and functional synaptic plasticity that occur in striatal projection neurons in PD and in l-DOPA-induced dyskinesia are specifically due to modulation of the neurotransmitter dopamine and are not artifacts of the use of chemical toxins in PD models. In addition, our findings provide evidence that synaptic plasticity in the Pitx3-/- mouse is similar to that seen in toxin models despite its lack of dopaminergic innervation of the striatum during development. Pitx3-/- mice reproduced the alterations described in patients with advanced PD and in well accepted toxin-based models of PD and dyskinesia. These results further consolidate the fidelity of the Pitx3-/- mouse as a PD model in which to study the morphological and physiological remodeling of striatal projection neurons by administration of l-DOPA and other drugs.

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          Author and article information

          Journal
          J. Neurosci.
          The Journal of neuroscience : the official journal of the Society for Neuroscience
          Society for Neuroscience
          1529-2401
          0270-6474
          Apr 11 2018
          : 38
          : 15
          Affiliations
          [1 ] Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28031 Madrid, Spain.
          [2 ] Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28031 Madrid, Spain moratalla@cajal.csic.es.
          Article
          JNEUROSCI.3184-17.2018
          10.1523/JNEUROSCI.3184-17.2018
          29483281

          aphakia, striatum, Parkinson's disease, dyskinesia, L-DOPA

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