title: 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.
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Barbara M L C
authors: BM
authors: Bocco
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: João Pedro
authors: JP
authors: Werneck-de-Castro
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Kelen C
authors: KC
authors: Oliveira
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Gustavo W
authors: GW
authors: Fernandes
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Tatiana L
authors: TL
authors: Fonseca
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Bruna P P
authors: BP
authors: Nascimento
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Elizabeth A
authors: EA
authors: McAninch
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Esther
authors: E
authors: Ricci
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Zsuzsanna
authors: Z
authors: Kvárta-Papp
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Csaba
authors: C
authors: Fekete
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Maria Martha
authors: MM
authors: Bernardi
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Balázs
authors: B
authors: Gereben
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Antonio C
authors: AC
authors: Bianco
authors: Division of Endocrinology and Metabolism (B.M.L.C.B., J.P.W.-d.C., G.W.F., T.L.F., E.A.M., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Translational Medicine (B.M.L.C.B., G.W.F., B.P.P.N.), Federal University of Sao Paulo, Sao Paulo SP, 04039-002, Brazil; Biophysics Institute and School of Physical Education and Sports (J.P.W.-d.C.), Federal University of Rio de Janeiro, RJ 21941-599, Brazil; Department of Clinic Endocrinology (K.C.O.), Federal University of Sao Paulo, Sao Paulo SP 04039-032, Brazil; Developmental Disorders Program (B.P.P.N., E.R., M.O.R.), Center of Biological Science and Health, Mackenzie Presbyterian University, Sao Paulo SP 01302-900 Brazil; Department of Endocrine Neurobiology (Z.K.-P., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes, and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; and Graduate Program of Environmental and Experimental Pathology (M.M.B.), Graduate Program of Dentistry, Universidade Paulista, Sao Paulo SP 04026-002, Brazil.
authors: Miriam O
authors: MO
authors: Ribeiro
mesh_terms: D000818:Animals; D001007:Anxiety / Q000201:enzymology*; D001253:Astrocytes / Q000201:enzymology*; D003863:Depression / Q000201:enzymology*; D015870:Gene Expression; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000172:deficiency* / Q000235:genetics; D008297:Male; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal / Q000502:physiology; D059467:Transcriptome; D014284:Triiodothyronine / Q000097:blood; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II