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

Mol Neurobiol. 2019 Jan;56(1):722-735. doi: 10.1007/s12035-018-1111-z. Epub 2018 May 23.


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.

Keywords: Amyloid peptide; Hippocampus; Hypothyroidism; Inflammation; Memory; Signaling pathways.

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Anxiety / complications
  • Anxiety / pathology
  • Behavior, Animal / drug effects
  • Biomarkers / metabolism*
  • Hippocampus / pathology*
  • Hypothyroidism / complications
  • Hypothyroidism / metabolism
  • Hypothyroidism / pathology
  • Hypothyroidism / physiopathology*
  • Male
  • Neuronal Plasticity / drug effects*
  • Propylthiouracil / pharmacology
  • Propylthiouracil / therapeutic use
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats, Wistar
  • Signal Transduction*
  • Spatial Memory / drug effects*
  • Thyroid Gland / drug effects
  • Thyroid Gland / pathology
  • Thyroid Hormones / pharmacology*
  • Thyroid Hormones / therapeutic use


  • Amyloid beta-Peptides
  • Biomarkers
  • RNA, Messenger
  • Thyroid Hormones
  • Propylthiouracil