HYPOTHYROIDISM IN THE ADULT RAT CAUSES AN INCREMENT OF BDNF IN THE BRAIN, NEURONAL AND ASTROCYTE APOPTOSIS, GLIOSIS AND DETERIORATION OF THE POSTSYNAPTIC DENSITY.

Background: Adult hypothyroidism is a highly prevalent condition that impairs processes, such as learning and memory. Even though T4 treatment can overcome the hypothyroidism in the majority of cases, it cannot fully recover the patient’s learning capacity and memory. In this work we analyzed the cellular and molecular changes in the adult brain occurring with the development of experimental hypothyroidism. Methods: Adult male Sprague-Dawley rats were treated with 6Propyl-2-thiouracil (PTU) for 20 days to induce hypothyroidism. Neuronal and astrocyte apoptosis were analyzed in the hippocampus of control and hypothyroid adult rats by confocal microscopy. The content of brain-derived neurotrophic factor (BDNF) was analyzed using ELISA and in situ hybridization. The glutamatergic synapse and the postsynaptic density (PSD) were analyzed by electron microscopy. The content of postsynaptic density proteins like tyrosine receptor kinase B (TrkB), p75 and N-methyl-D-aspartate receptor (NMDAr) were analyzed by immunoblot. Results: We observed that the hippocampus of hypothyroid adult rats displayed increased apoptosis levels in neurons and astrocyte, as well as reactive gliosis as compared to controls. Moreover, we found that the amount of BDNF mRNA was higher in the hippocampus of hypothyroid rats and the content of TrkB, the receptor for BDNF, was reduced at the PSD of the CA3 region of hypothyroid rats as compared controls. We also observed that the glutamatergic synapses from the stratum radiatum of CA3 from hypothyroid rats, contained thinner PSDs than control rats. This observation was in agreement with a reduced content of NMDAr subunits at the PSD in hypothyroid animals. Conclusions: Our data suggest that adult hypothyroidism affects the hippocampus by a mechanism that alters the composition of PSD, reduces neuronal and astrocyte survival and alters the content of the signaling neurotrophic factors, such as BDNF. Page 3 of 36

[1]  Zheng Zachory Wei,et al.  Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer's disease. , 2011, Current Alzheimer research.

[2]  C. Liapi,et al.  Structural and functional alterations in the hippocampus due to hypothyroidism , 2010, Metabolic Brain Disease.

[3]  B. Lu,et al.  New Insights in the Biology of BDNF Synthesis and Release: Implications in CNS Function , 2009, The Journal of Neuroscience.

[4]  N. Unsain,et al.  Brain‐derived neurotrophic factor facilitates TrkB down‐regulation and neuronal injury after status epilepticus in the rat hippocampus , 2009, Journal of neurochemistry.

[5]  S. Mullally,et al.  Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. , 2009, The Journal of clinical endocrinology and metabolism.

[6]  C. Aceves,et al.  The maintenance of hippocampal pyramidal neuron populations is dependent on the modulation of specific cell cycle regulators by thyroid hormones , 2009, Brain Research.

[7]  K. Alzoubi,et al.  Levothyroxin restores hypothyroidism‐induced impairment of hippocampus‐dependent learning and memory: Behavioral, electrophysiological, and molecular studies , 2009, Hippocampus.

[8]  D. Rubello,et al.  Neurological and psychiatric disorders in thyroid dysfunctions. The role of nuclear medicine: SPECT and PET imaging. , 2008, Minerva endocrinologica.

[9]  Xueyi Xie,et al.  Inherited tertiary hypothyroidism in Sprague–Dawley rats , 2007, Brain Research.

[10]  J. Bernal.  Thyroid hormone receptors in brain development and function , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[11]  J. G. Nicholls,et al.  Optical recording from respiratory pattern generator of fetal mouse brainstem reveals a distributed network , 2006, Neuroscience.

[12]  A. Pietrzykowski,et al.  Dynamic nongenomic actions of thyroid hormone in the developing rat brain. , 2006, Endocrinology.

[13]  J. Tijssen,et al.  Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. , 2005, European journal of endocrinology.

[14]  K. Alzoubi,et al.  Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: Electrophysiological and molecular studies , 2005, Experimental Neurology.

[15]  R. Cuppini,et al.  Thyroid Hormones Affect Neurogenesis in the Dentate Gyrus of Adult Rat , 2005, Neuroendocrinology.

[16]  Bai Lu,et al.  Activation of p75NTR by proBDNF facilitates hippocampal long-term depression , 2005, Nature Neuroscience.

[17]  R. Vaidya,et al.  Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain , 2005, Molecular and Cellular Neuroscience.

[18]  Barbara L. Hempstead,et al.  ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin , 2005, The Journal of Neuroscience.

[19]  Laura A. Mamounas,et al.  Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression , 2004, Journal of Neuroscience Methods.

[20]  M. Bauer,et al.  Thyroid, brain and mood modulation in affective disorder: insights from molecular research and functional brain imaging. , 2003, Pharmacopsychiatry.

[21]  J. Silva.  The Thermogenic Effect of Thyroid Hormone and Its Clinical Implications , 2003, Annals of Internal Medicine.

[22]  J. Berman,et al.  MCP‐1 (CCL2) protects human neurons and astrocytes from NMDA or HIV‐tat‐induced apoptosis , 2003, Journal of neurochemistry.

[23]  E. Hirsch,et al.  The Role of Glial Reaction and Inflammation in Parkinson's Disease , 2003, Annals of the New York Academy of Sciences.

[24]  M. Chao,et al.  Neurotrophins and their receptors: A convergence point for many signalling pathways , 2003, Nature Reviews Neuroscience.

[25]  D. Brady,et al.  Thyroid Hormone Regulation of N‐Methyl‐d‐Aspartic Acid Receptor Subunit mRNA Expression in Adult Brain , 2003, Journal of neuroendocrinology.

[26]  F. Chiodi,et al.  Astrocyte Activation and Apoptosis: Their Roles in the Neuropathology of HIV Infection , 2003, Brain pathology.

[27]  Y. Barde,et al.  The neurotrophin receptor p75NTR: novel functions and implications for diseases of the nervous system , 2002, Nature Neuroscience.

[28]  L. Givalois,et al.  Osmotic stress increases brain-derived neurotrophic factor messenger RNA expression in the hypothalamic supraoptic nucleus with differential regulation of its transcripts. Relation to arginine–vasopressin content , 2002, Neuroscience.

[29]  R. Ehrlich,et al.  Psychoeducational outcome in children with early-treated congenital hypothyroidism , 2000, Pediatrics.

[30]  F. Rage,et al.  Negative regulation of brain-derived neurotrophic factor mRNA expression by kainic acid in substantia nigra. , 1999, Brain research. Molecular brain research.

[31]  V. M. Neto,et al.  Cerebellar astrocytes treated by thyroid hormone modulate neuronal proliferation , 1999, Glia.

[32]  R. Wenthold,et al.  Relationship between N-Methyl-D-aspartate Receptor NR1 Splice Variants and NR2 Subunits* , 1996, The Journal of Biological Chemistry.

[33]  M. Álvarez-Dolado,et al.  Expression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain. , 1994, Brain research. Molecular brain research.

[34]  O. Lindvall,et al.  Coexpression of neurotrophins and their receptors in neurons of the central nervous system. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[35]  N. Wohllk,et al.  [Treatment of hyperthyroidism during pregnancy: experience with 19 cases]. , 1993, Revista medica de Chile.

[36]  M. Saarma,et al.  Multiple promoters direct tissue-specific expression of the rat BDNF gene , 1993, Neuron.

[37]  J. P. Andrade,et al.  Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: A morphometric study , 1991, The Journal of comparative neurology.

[38]  P. K. Smith,et al.  Measurement of protein using bicinchoninic acid. , 1985, Analytical biochemistry.

[39]  J. Legrand.  [Analysis of the morphogenetic action of thyroid hormones on the cerebellum of young rats]. , 1967, Archives d'anatomie microscopique et de morphologie experimentale.

[40]  A. Heinz,et al.  Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain , 2002, Molecular Psychiatry.

[41]  J. Dussault,et al.  Thyroid hormones and brain development. , 1987, Annual review of physiology.