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Changes in Dendritic Spine Density and Inhibitory Perisomatic Connectivity onto Medium Spiny Neurons in l-Dopa-Induced Dyskinesia

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Abstract

Using bacterial artificial chromosome–double transgenic mice expressing tdTomato in D1 receptor-medium spiny neurons (MSNs) and enhanced green fluorescent protein in D2 receptor-MSNs, we have studied changes in spine density and perisomatic GABAergic boutons density in MSNs of both the D1R and D2R pathways, in an experimental model of parkinsonism (mouse injected with 6-hydroxydopamine in the medial forebrain bundle), both in the parkinsonian and dyskinetic condition induced by l-DOPA treatment. To assess changes in perisomatic GABAergic connectivity onto MSNs, we measured the number of contacts originated from parvalbumin (PV)-containing striatal “fast-spiking” interneurons (FSIs), the major component of a feed-forward inhibition mechanism that regulates spike timing in MSNs, in both cell types as well as the number of vesicular GABA transporter (VGAT) contacts. Furthermore, we determined changes in PV-immunoreactive cell density by PV immunolabeling combined with Wisteria floribunda agglutinin (WFA) labeling to detect FSI in a PV-independent manner. We also explored the differential expression of striatal activity–regulated cytoskeleton-associated protein (Arc) and c-Fos in both types of MSNs as a measure of neuronal activation. Our results confirm previous findings of major structural changes in dendritic spine density after nigrostriatal denervation, which are further modified in the dyskinetic condition. Moreover, the finding of differential modifications in perisomatic GABAergic connectivity and neuronal activation in MSNs suggests an attempt by the system to regain homeostasis after denervation and an imbalance between excitation and inhibition leading to the development of dyskinesia after exposure to l-DOPA.

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Acknowledgements

The authors would like to thank Germán La Iacona for his technical assistance.

Funding

This work was supported by grants from the Argentine Agency for the Promotion of Science (PICT 2011-1758 and PICT 2015-3687), University of Buenos Aires (UBACyT 2014-2017 249), and Argentine National Research Council (CONICET, PIP 2013-0401) and by grants from the Spanish Ministries of Economía, Industria y Competitividad (SAF2016-78207-R) and PCIN-2015-098 and of Sanidad Servicios Sociales e Igualdad (ISCIII, CIBERNED CB06/05/0055, PNSD2016I033) and 172275 from Ramón Areces Foundation to RM. GG is a research fellow of the CONICET. LR, JEB, MGM, and IRET are members of the research career of CONICET.

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Authors and Affiliations

  1. Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina

    G. Gomez, O. S. Gershanik & I. R. E. Taravini

  2. Instituto de Investigaciones Farmacológicas (ININFA), Laboratorio de Parkinson Experimental, CONICET - Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina

    G. Gomez, O. S. Gershanik & I. R. E. Taravini

  3. Instituto de Fisiología y Biofísica (IFIBIO) Bernardo Houssay, Grupo de Neurociencia de Sistemas, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina

    M. V. Escande, L. Rela, J. E. Belforte & M. G. Murer

  4. Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

    L. M. Suarez & R. Moratalla

  5. CIBERNED, Instituto de Salud Carlos III, Madrid, Spain

    L. M. Suarez & R. Moratalla

  6. Laboratorio de Neurobiología Experimental (LNE), CONICET - Facultad de Bromatología, Universidad Nacional de Entre Ríos, Gualeguaychú, Entre Ríos, Argentina

    I. R. E. Taravini

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  1. G. Gomez
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Correspondence to I. R. E. Taravini.

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All surgical procedures and experimental manipulations were performed in accordance with European Council Directive 2010/63/EU guidelines for the care of laboratory animals and the regulations for the Care and Use of Laboratory Animals of the National Institutes of Health, USA. Animal experiments were approved by our local Ethics Committee (IACUC EXP-UBA No. 0027665/2014).

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Gomez, G., Escande, M.V., Suarez, L.M. et al. Changes in Dendritic Spine Density and Inhibitory Perisomatic Connectivity onto Medium Spiny Neurons in l-Dopa-Induced Dyskinesia. Mol Neurobiol 56, 6261–6275 (2019). https://doi.org/10.1007/s12035-019-1515-4

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  • DOI: https://doi.org/10.1007/s12035-019-1515-4

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