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Dysbindin-1A modulation of astrocytic dopamine and basal ganglia dependent behaviors relevant to schizophrenia

Molecular Psychiatry volume 27, pages 4201–4217 (2022)Cite this article

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Abstract

The mechanisms underlying the dichotomic cortical/basal ganglia dopaminergic abnormalities in schizophrenia are unclear. Astrocytes are important non-neuronal modulators of brain circuits, but their role in dopaminergic system remains poorly explored. Microarray analyses, immunohistochemistry, and two-photon laser scanning microscopy revealed that Dys1 hypofunction increases the reactivity of astrocytes, which express only the Dys1A isoform. Notably, behavioral and electrochemical assessments in mice selectively lacking the Dys1A isoform unraveled a more prominent impact of Dys1A in behavioral and dopaminergic/D2 alterations related to basal ganglia, but not cortical functioning. Ex vivo electron microscopy and protein expression analyses indicated that selective Dys1A disruption might alter intracellular trafficking in astrocytes, but not in neurons. In agreement, Dys1A disruption only in astrocytes resulted in decreased motivation and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. These processes might have clinical relevance because the caudate, but not the cortex, of patients with schizophrenia shows a reduction of the Dys1A isoform. Therefore, we started to show a hitherto unknown role for the Dys1A isoform in astrocytic-related modulation of basal ganglia behavioral and dopaminergic phenotypes, with relevance to schizophrenia.

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Fig. 1: Dys1 modulates astrocytic reactivity.
Fig. 2: Dys1A disruption impairs basal ganglia- but not PFC-dependent behaviors.
Fig. 3: Dys1A alters the dopaminergic system within basal ganglia but not PFC.
Fig. 4: Dys1A disruption alters vesicular trafficking and Golgi complex morphology in basal ganglia astrocytes.
Fig. 5: Dys1A disruption in astrocytes induce sensorimotor gating and motivational deficits, decrease basal ganglia dopamine, and increase astrocytic D2 receptors.

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Acknowledgements

We thank M. Morini, E. Albanesi, D. Cantatore, G. Pruzzo, T. Catelani, D. Mauro, S. Monari, F. Torri, B. Chiarenza, A. Monteforte and C. Chiabrera, for technical support. We thank GlaxoSmithKline and Dr S. Wilson for generously donating the newly generated Dys1Aflox mice. We thank Dr D.R. Weinberger and Dr R.E. Straub for initial access to the Brain Cloud databank. This work was supported by funding from the Marie Sklodowska-Curie Fellowships (grant n.796244) to CD; the Ministero dell’Universita’ e della Ricerca italiano (project PRIN 2017K2NEF4) to FD; grant MIUR Progetto eccellenza to FF; the Istituto Italiano di Tecnologia, the Brain and Behavior Research Foundation (2015 NARSAD grant n.23234), the Ministero della Salute italiano (project GR-2016-02362413), and Fondazione Telethon Italia (project GGP19103) to FP.

Author information

Author notes

  1. These authors contributed equally: Rosa Mastrogiacomo, Gabriella Trigilio.

  2. These authors jointly supervised this work: Francesca Managò, Francesco Papaleo.

Authors and Affiliations

  1. Genetics of Cognition laboratory, Neuroscience area, Istituto Italiano di Tecnologia, via Morego, 30, 16163, Genova, Italy

    Rosa Mastrogiacomo, Gabriella Trigilio, Céline Devroye, Daniel Dautan, Valentina Ferretti, Roberto Marotta, Federica Maltese, Enrica Vitali, Giada Pacinelli, Francesca Managò & Francesco Papaleo

  2. Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy

    Gabriella Trigilio, Filippo Drago & Gian Marco Leggio

  3. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy

    Daniel Dautan & Francesco Papaleo

  4. Neuroscience Institute, CNR, Padova, Italy

    Gabriele Losi, Annamaria Lia & Giorgio Carmignoto

  5. Department of Biomedical Science, University of Padova, Padova, Italy

    Gabriele Losi, Annamaria Lia & Giorgio Carmignoto

  6. Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy

    Lucia Caffino & Fabio Fumagalli

  7. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy

    Genny Orso & Alessia Forgiarini

  8. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    Gessica Piras & Maria Antonietta De Luca

  9. Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia

    Debora A. Rothmond & Cynthia S. Weickert

  10. School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland

    John L. Waddington

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Contributions

Conceptualization, RM, GT, and FP; Methodology and Investigation, RM, GT, DD, CD, GL, AL, LC, FF, VF, GO, RM, FM, GP, AF, GC, MADL, FM, and FP; Resources, GO, DR, JLW, GML, GC, CSW, and FP; Writing, all authors; Visualization, RM, GT, DD, CD, GL, AL, GL, GO, RM, FM, and FP; Supervision, FP; Funding Acquisition, FD, CSW, and FP.

Corresponding authors

Correspondence to Francesca Managò or Francesco Papaleo.

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Mastrogiacomo, R., Trigilio, G., Devroye, C. et al. Dysbindin-1A modulation of astrocytic dopamine and basal ganglia dependent behaviors relevant to schizophrenia. Mol Psychiatry 27, 4201–4217 (2022). https://doi.org/10.1038/s41380-022-01683-8

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