Research Report The maintenance of hippocampal pyramidal neuron populations is dependent on the modulation of specific cell cycle regulators by thyroid hormones Claudia Alva-Sánchez a , Karla Sánchez-Huerta a , Omar Arroyo-Helguera b , Brenda Anguiano b , Carmen Aceves b , Jorge Pacheco-Rosado a, ⁎ a Departamento de Fisiología “Mauricio Russek”, Escuela Nacional de Ciencias Biológicas-IPN, Prol. de Carpio y Plan de Ayala, C.P. 11340, D.F. México, Mexico b Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, UNAM-Juriquilla, Querétaro, Mexico ARTICLE INFO ABSTRACT Article history: Accepted 12 February 2009 Available online 6 March 2009 The onset of adult hypothyroidism causes neuronal damage in the CA3 hippocampal region, which is attenuated by T 4 administration. We analyzed the expression of molecular proliferation markers (Cyclin D1 and PCNA), cellular damage-arrest (p53 and p21), and apoptosis (Bax/Bcl-2 index) in the hippocampus of hypothyroid (methimazole; 60 mg/kg) or thyroid replaced (T 4 , 20 μg/kg; MMI+T 4 or T 3 , 20 μg/kg; MMI+T 3 ) adult male rats. Histological analysis showed that hypothyroid animals exhibit significant neuronal damage in all regions of the hippocampus accompanied by the triggering of the apoptotic pathway (increases in p53, p21 and the Bax/Bcl-2 index) and no changes in proliferation (Cyclin D1 and PCNA). MMI+T 4 replaced animals were completely protected with no changes in molecular markers. In contrast, MMI+T 3 replaced animals showed partial protection in which, although pro-apoptotic effects remained (increase in the Bax/Bcl-2), proliferative mechanisms were triggered (increase in p53, Cyclin D1 and PCNA expression). Our results indicate that thyroid hormones participate in the maintenance of the hippocampal neuronal population even in adulthood, suggesting that THs have different physiological roles as neuronal survival factors: T 4 prevents the activation of apoptotic pathways, whereas T 3 activates cell differentiation and proliferation mechanisms. © 2009 Elsevier B.V. All rights reserved. Keywords: Apoptosis Cycline D1 PCNA Bax/Bcl-2 Hypothyroidism 1. Introduction Thyroid hormones (THs) are essential for maturation and function during the development of the central nervous system (CNS) in vertebrates. THs deficiency during develop- ment leads to irreversible brain damage resulting in mental retardation (Bernal, 1999; Lima et al., 2001; Porterfield and Hendrich, 1993). The active hormone triiodothyronine (T 3 ) binds nuclear receptors that function as ligand-modulated transcription factors and regulate patterns of gene expression. BRAIN RESEARCH 1271 (2009) 27 – 35 ⁎ Corresponding author. Fax: +52 55 5729 6206. E-mail addresses: Jpacheco@encb.ipn.mx, Jprosado@hotmail.com (J. Pacheco-Rosado). Abbreviations: 5′D, 5′-deiodination; AIF, apoptosis inducing factor; CD1, cycline D1; CNS, central nervous system; D2, deiodinase type 2; DTT, dithiothreitol; hD2, hippocampal deiodinase type 2; MMI, methimazole; PCNA, proliferating cell nuclear antigen; PTU, 6-n-propyl-2- thiouracil; T3, 3,5,3′-triiodothyronine; T4, thyroxine; THs, thyroid hormones 0006-8993/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2009.02.043 available at www.sciencedirect.com www.elsevier.com/locate/brainres