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Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and β-Amyloid Peptide Load in Hypothyroid Rats

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Abstract

Hypothyroidism is a condition that becomes more prevalent with age. Patients with untreated hypothyroidism have consistently reported symptoms of severe cognitive impairments. In patients suffering hypothyroidism, thyroid hormone supplementation offers the prospect to alleviate the cognitive consequences of hypothyroidism; however, the therapeutic value of TH supplementation remains at present uncertain and the link between cellular modifications associated with hypothyroidism and neurodegeneration remains to be elucidated. In the present study, we therefore evaluated the molecular and behavioral consequences of T3 hormone replacement in an animal model of hypothyroidism. We have previously reported that the antithyroid molecule propylthiouracil (PTU) given in the drinking water favors cerebral atrophy, brain neuroinflammation, Aβ production, Tau hyperphosphorylation, and altered plasticity-related cell-signaling pathways in the hippocampus in association with hippocampal-dependent spatial memory deficits. In the present study, our aim was to explore, in this model, the effect of hippocampal T3 signaling normalization on various molecular mechanisms involved in learning and memory that goes awry under conditions of hypothyroidism and to evaluate its potential for recovery of hippocampal-dependent memory deficits. We report that T3 supplementation can alleviate hippocampal-dependent memory impairments displayed by hypothyroid rats and normalize key markers of thyroid status in the hippocampus, of neuroinflammation, Aβ production, and of cell-signaling pathways known to be involved in synaptic plasticity and memory function. Together, these findings suggest that normalization of hippocampal T3 signaling is sufficient to reverse molecular and cognitive dysfunctions associated with hypothyroidism.

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Acknowledgements

We would like to thank Pascale Gisquet-Verrier for her help with behavioral equipment and Fabien Lhericel for animal care.

Funding

This work was supported by Centre National de la Recherche Scientifique (France), University Paris-Sud (France) and by the France Alzheimer/Fédération pour la Recherche sur le Cerveau (AAP France Alzheimer 2013) to V Enderlin. A Chaalal was supported by a doctoral fellowship from the French Ministry of Research.

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  1. Neuroscience Paris-Saclay Institute (Neuro-PSI), UMR 9197, CNRS, University Paris-Sud, University Paris-Saclay, F-91405, Orsay, France

    Amina Chaalal, Roseline Poirier, Serge Laroche & Valérie Enderlin

  2. Institut National de la Santé et de la Recherche Medicale (INSERM), CHU-Lille, UMR-S 1172, Alzheimer and Tauopathies, LabEx DISTALZ, University Lille, F-59000, Lille, France

    David Blum

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  1. Amina Chaalal
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Chaalal, A., Poirier, R., Blum, D. et al. Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and β-Amyloid Peptide Load in Hypothyroid Rats. Mol Neurobiol 56, 722–735 (2019). https://doi.org/10.1007/s12035-018-1111-z

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