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Gestational Hypothyroxinemia Affects Glutamatergic Synaptic Protein Distribution and Neuronal Plasticity Through Neuron-Astrocyte Interplay

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Abstract

Gestational hypothyroxinemia, characterized by low levels of maternal thyroxine (T4) during gestation, is closely associated with cognitive impairment in offspring. Studies in animal models have shown that this condition alters neuronal glutamatergic synapses in the hippocampus. Given that astrocytes critically contribute to the establishment and functioning of synapses, the aim of this study was to determine the effects of gestational hypothyroxinemia on the capacity of astrocytes to regulate glutamatergic synapses. In an in vitro co-culture model of astrocytes and hippocampal neurons, gestational hypothyroxinemia profoundly affected the synaptic patterns of GluN1 and CD3ζ in an astrocyte-dependent manner. These effects were associated with impaired plasticity that was dependent on both neuronal and astrocyte contributions. These results highlight the importance of neuron-astrocyte interplay in the deleterious effects of gestational hypothyroxinemia and the timely diagnosis and treatment of this condition during gestation to ensure proper central nervous system development in offspring.

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Acknowledgments

This study was supported by funding awarded by the Fondo Nacional de Desarrollo Científico y Tecnológico de Chile (FONDECYT Projects 1130996, 1140010, 1110604, 1100971, 1131012, and 1110397), the Millennium Institute on Immunology and Immunotherapy P09/016-F, and the La Région Pays De La Loire through the “Nouvelles Equipes-nouvelles thématiques” Grant. AMK is a Chaire De La Région Pays De La Loire, Chercheur Étranger D'excellence, France. Additional funding was also received from the Comité de Evaluación y Orientación de la Cooperación Científica con Chile del Gobierno de Francia (ECOS)-Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) Grant C11S03 through the CONICYT-Instituto Nacional de Salud y de Investigación Médica de Francia (INSERM) Program, the Universidad Andrés Bello (UNAB) Proyecto Inicio DI-31/11R, and the Proyecto Nucleo UNAB DI-471-15/N.

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Authors and Affiliations

  1. Millennium Institute on Immunology and Immunotherapy, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile

    Pablo Cisternas & Claudia A. Riedel

  2. INSERM Unité Mixte de Recherche 1064, Institut Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire Nantes, Nantes, France

    Antoine Louveau, Susan M. Bueno, Alexis M. Kalergis & Hélène Boudin

  3. Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    Susan M. Bueno & Alexis M. Kalergis

  4. Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Alexis M. Kalergis

  5. INSERM Unité de Recherche 913, L’Institut des Maladies de l’Appareil Digestif, Université de Nantes, 44035, Nantes, France

    Hélène Boudin

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  1. Pablo Cisternas
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  2. Antoine Louveau
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  3. Susan M. Bueno
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  4. Alexis M. Kalergis
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  5. Hélène Boudin
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  6. Claudia A. Riedel
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Corresponding authors

Correspondence to Hélène Boudin or Claudia A. Riedel.

Electronic supplementary material

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Supplementary Figure 1

Experimental timeline and groups. Scheme of the experimental timeline. Red and blue rectangles = pregnant rats; MMI = methimazole-treated rats; IF = immunofluorescence; C = control group; H = hypothyroxinemia group; DIV = days in vitro; CA = astrocytes derived from control-gestated rats; HA = astrocytes derived from hypothyroxinemia-gestated rats; CN = neurons derived from control-gestated rats; and HN = neurons derived from hypothyroxinemia-gestated rats. CACN, CAHN, HACN, and HAHN represent the four types of co-cultures analyzed. (GIF 43 kb)

High resolution image (TIF 117 kb)

Supplementary Figure 2

GFAP content and distribution remains normal in hypothyroxinemia-derived astrocytes. (a) Representative photographs of control-derived astrocytes (CA) and (b) hypothyroxinemia-derived astrocytes (HA) showing glial fibrillary acidic protein (GFAP) distribution. (c) Quantification of GFAP distribution. The results are shown as the mean ± SEM of n = 3. No significant differences were found (p = not statically significant). Scale bar = 30 μm. (d) Representative Western blots for GFAP of CA and HA. (e) Quantification of GFAP content. The results are shown as the mean ± SEM of n = 3. No significant differences were found (p = not statically significant) (GIF 69 kb)

High resolution image (TIF 306 kb)

Supplementary Figure 3

Full-size western blot for syn-1, PSD-95 and GluN1. Representative western blots for (a) syn-1 (90 kDa), (b) PSD-95 (95 kDa), (c) GluN1 (116 kDa), and actin (43 kDa). Protein content is visualized for four experimental groups CACN = control astrocytes, control neurons; CAHN = control astrocytes, hypothyroxinemia-derived neurons; HACN = hypothyroxinemia-derived astrocytes, control neurons; and HAHN = hypothyroxinemia-derived astrocytes, hypothyroxinemia-derived neurons (GIF 55 kb)

High resolution image (TIF 278 kb)

Supplementary Table 1

Cluster size for syn-1, PSD-95, GluN1 and CD3ζ. The size of clusters were analyzed in neurons co-cultured with astrocytes in the following four experimental groups: CACN = control astrocytes, control neurons; CAHN = control astrocytes, hypothyroxinemia-derived neurons; HACN = hypothyroxinemia-derived astrocytes, control neurons; and HAHN = hypothyroxinemia-derived astrocytes, hypothyroxinemia-derived neurons. Data are presented as the mean size (um2) ± SE. * indicates significant differences, where p < 0.05 Kruskal-Wallis with Dunn’s posttest for GluN1 and p < 0.05 one-way ANOVA with Tukey's posttest for Syn, PSD95 and CD3ζ . Experimental n are 12 for syn-1, 4 for PSD95 and 8 for both GluN1 and CD3ζ (GIF 33 kb)

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Cisternas, P., Louveau, A., Bueno, S.M. et al. Gestational Hypothyroxinemia Affects Glutamatergic Synaptic Protein Distribution and Neuronal Plasticity Through Neuron-Astrocyte Interplay. Mol Neurobiol 53, 7158–7169 (2016). https://doi.org/10.1007/s12035-015-9609-0

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