Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice

Abstract

Millions of levothyroxine-treated hypothyroid patients complain of impaired cognition despite normal TSH serum levels. This could reflect abnormalities in the type 2 deiodinase (D2)-mediated T4-to-T3 conversion, given their much greater dependence on the D2 pathway for T3 production. T3 normally reaches the brain directly from the circulation or is produced locally by D2 in astrocytes. Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) have normal serum T3 but exhibit anxiety-depression-like behavior as found in open field and elevated plus maze studies and when tested for depression using the tail-suspension and the forced-swimming tests. Remarkably, 4 weeks of daily treadmill exercise sessions eliminated this phenotype. Microarray gene expression profiling of the Astro-D2KO hippocampi identified an enrichment of three gene sets related to inflammation and impoverishment of three gene sets related to mitochondrial function and response to oxidative stress. Despite normal neurogenesis, the Astro-D2KO hippocampi exhibited decreased expression of four of six known to be positively regulated genes by T3, ie, Mbp (∼43%), Mag (∼34%), Hr (∼49%), and Aldh1a1 (∼61%) and increased expression of 3 of 12 genes negatively regulated by T3, ie, Dgkg (∼17%), Syce2 (∼26%), and Col6a1 (∼3-fold) by quantitative real-time PCR. Notably, in Astro-D2KO animals, there was also a reduction in mRNA levels of genes known to be affected in classical animal models of depression, ie, Bdnf (∼18%), Ntf3 (∼43%), Nmdar (∼26%), and GR (∼20%), which were also normalized by daily exercise sessions. These findings suggest that defects in Dio2 expression in the brain could result in mood and behavioral disorders.

Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain

“…There is ample evidence that ER stress/UPR (49) and disruption of T3-TR signaling (50) can interfere with neuronal function and lead to impaired cognition. For example, mice with astrocyte-specific inactivation of Dio2 are systemically euthyroid, but exhibit anxiety-depressive-like behavior due to generalized hypothyroidism in the brain (51). In addition, a transgenic mouse bearing a mutant TRβ1 is systemically euthyroid, but displays behavioral abnormalities, such as inattention, hyperactivity, and contrast, Ala92-D2 HY causes ER stress and can be easily visualized in the trans-Golgi (Figure 1, G-L).…”

Increased aggression and lack of maternal behavior in Dio3‐deficient mice are associated with abnormalities in oxytocin and vasopressin systems

“…) and mouse models have demonstrated that genetic and pharmacological manipulations leading to altered T3 action in the brain modify anxiety‐ and depression‐like behaviors (Bocco et al . ; Buras et al . ; Darbra et al .…”

“…Thyroid hormone action is of particular importance for the development and function of the central nervous system (Bernal 2005) and it influences behavior. Abnormal thyroid hormone states in humans are associated with mood disorders (Chueire et al 2007;Cleare et al 1995;Constant et al 2005;Custro et al 1994;Sinai et al 2009) and mouse models have demonstrated that genetic and pharmacological manipulations leading to altered T3 action in the brain modify anxiety-and depression-like behaviors (Bocco et al 2016;Buras et al 2014;Darbra et al 2003;Galton et al 2007;Ge et al 2014;Shukla et al 2010;Stohn et al 2016;Venero et al 2005;Yu et al 2015;Zeng et al 2007).…”

Temporal Pole Responds to Subtle Changes in Local Thyroid Hormone Signaling

“…It is unexpected that the intensity of T3S + also did not correlate with the expression of deiodinases ( Table 2 ). Glia-specific D2KO animals exhibit a phenotype of brain hypothyroidism [ 40 ] and the global D3KO mouse exhibit a phenotype of brain thyrotoxicosis [ 41 , 42 ]. At face value, this suggests that within this narrow range of TH signaling in the human brain, deiodinases play a more homeostatic role preserving TH signaling, rather than defining it.…”