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

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 T-4-to-T-3 conversion, given their much greater dependence on the D2 pathway for T-3 production. T-3 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 T-3 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 T-3, ie, Mbp (similar to 43%), Mag (similar to 34%), Hr (similar to 49%), and Aldh1a1 (similar to 61%) and increased expression of 3 of 12 genes negatively regulated by T-3, ie, Dgkg (similar to 17%), Syce2 (similar to 26%), and Col6a1 (similar to 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 (similar to 18%), Ntf3 (similar to 43%), Nmdar (similar to 26%), and GR (similar to 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.National Institute of Diabetes and Digestive and Kidney Diseases [R01 65055]Hungarian Brain Research Program Grant [NAP A I/3-4]Coordination for the Improvement of Higher Education Personnel Grant, Coordination for the Improvement of Higher Education Personnel (CAPES), BrazilRush Univ, Med Ctr, Div Endocrinol & Metab, 1735 West Harrison St, Chicago, IL 60612 USAUniv Fed Sao Paulo, Dept Translat Med, BR-04039002 Sao Paulo, SP, BrazilUniv Fed Rio de Janeiro, Inst Biophys, BR-21941599 Rio De Janeiro, RJ, BrazilUniv Fed Rio de Janeiro, Sch Phys Educ & Sports, BR-21941599 Rio De Janeiro, RJ, BrazilUniv Fed Sao Paulo, Dept Clin Endocrinol, BR-04039032 Sao Paulo, SP, BrazilUniv Prebiteriana Mackenzie, Ctr Biol Sci & Hlth, Dev Disorders Program, Rua Consolacao 930, BR-01302900 Sao Paulo, SP, BrazilHungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, H-1083 Budapest, HungaryTufts Med Ctr, Tupper Res Inst, Div Endocrinol Diabet & Metab, Dept Med, Boston, MA 02111 USAUniv Paulista, Grad Program Dent, Grad Program Environm & Expt Pathol, BR-04026002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Translat Med, BR-04039002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Clin Endocrinol, BR-04039032 Sao Paulo, SP, BrazilNIDDK:R01 65055Web of Scienc