A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation

Abstract

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism and neuroinflammation, from a protective perspective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized that WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulatisng TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of the hippocampal TH regulatory system over TH circulating levels in the hippocampal glial reactivity.

Defective thyroid hormone transport to the brain leads to astroglial alterations

“…Given the importance of THs action during astrocyte development, as well as recent evidence suggesting that hypothyroidism might lead to gliosis (22)(23)(24), in this work we have evaluated possible alterations in the astroglial population including a potential state of astrogliosis as an additional pathological mechanism mediating the severe neurological impairments in MCT8-de cient patients.…”

“…Indeed, there is increasing evidence indicating that brain hypothyroidism leads to astrogliosis. It has been observed that hypothyroidism induced by anti-thyroid drugs increases the number of GFAP + cells in the cortex (22) and hippocampus (22,24) and that brain-hypothyroid-mice de cient in MCT8 and the organic anion transporting protein OATP1C1 present an elevated number of astrocytes in the corpus callosum (23). Our ndings further support this emerging body of literature linking hypothyroidism to astrogliosis and extend these observations to humans.…”

“…Astrocytes also express the enzyme deiodinase 2 (DIO2) which locally generates the main cerebral pool of T3 from T4 (21). There is recent evidence suggesting that brain hypothyroidism leads to astrogliosis (22)(23)(24). Astrogliosis is a reaction of astrocytes to disturbed homeostasis in the brain, with changes in the number of astrocytes, their morphology, and function.…”

Thyroid hormone action in adult neurogliogenic niches: the known and unknown

“…Adult-onset hyperthyroidism compromised learning and memory function and increased anxiety in rats and mice (98,99). Likewise, hypothyroidism in adult rodents either by thyroidectomy or administration of PTU or MMI as well as a low iodine diet resulted in an anxiety-depressionlike state as well as impaired learning and spatial memory performance (20,(100)(101)(102)(103). Why adult-onset hypo-and hyperthyroidism culminate in similar behavior impairments remains elusive.…”