La versión final de este artículo es de uso interno de la institución.
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


TGF-β1 is an anti-inflammatory cytokine that is augmented in the brain of autistic patients and that can affect brain development. In this work, we studied the effects of overexpressing TGF-β1 in the dentate gyrus of adult or young mice on behavior. TGF-β1 overexpression during postnatal development led to a long-term decrease in social interaction and to long-term increases in self-grooming and depression-related behaviors. Our analysis shows that these behavioral changes correlate with the long-term downregulation of TGF-β1 and IL-6 expression in the dentate gyrus, as well as to decreases in the mRNA levels of the synaptic protein neuroligin 3 and in the number of Reelin-positive neurons in the dentate gyrus. In contrast, chronic expression of TGF-β1 during adulthood led to transient opposite effects on these behaviors. These results show a central role of hippocampal TGF-β1 in the programming and modulation of social interaction, repetitive behavior and depression-related behavior. Finally, our data suggest a role of hippocampal TGF-β1 and early-life neuroinflammation in the development of the behavioral alterations observed in autism spectrum disorders. © 2011 Elsevier Inc.


Documento: Artículo
Título:Early and adult hippocampal TGF-β1 overexpression have opposite effects on behavior
Autor:Depino, A.M.; Lucchina, L.; Pitossi, F.
Filiación:Institute for Physiology, Molecular Biology and Neurosciences, CONICET-UBA, C1428EHA Buenos Aires, Argentina
Department of Physiology, Molecular and Cellular Biology, FCEyN, University of Buenos Aires, C1428EHA Buenos Aires, Argentina
Leloir Institute Foundation, Institute for Biochemical Investigations, CONICET, 1405 Buenos Aires, Argentina
Palabras clave:Autism; Behavior; Mice; Neuroinflammation; Postnatal programming; Transforming Growth Factor-beta 1; interleukin 6; neuroligin; reelin; transforming growth factor beta1; animal experiment; article; behavior; compulsion; controlled study; dentate gyrus; depression; gene overexpression; grooming; hippocampus; male; mouse; nerve cell; nonhuman; priority journal; protein expression; social interaction; Adenoviridae; Animals; Behavior, Animal; Depression; Female; Gliosis; Grooming; Hindlimb Suspension; Hippocampus; Immunohistochemistry; Interpersonal Relations; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pregnancy; Real-Time Polymerase Chain Reaction; RNA, Messenger; Stereotaxic Techniques; Swimming; Transforming Growth Factor beta1
Página de inicio:1582
Página de fin:1591
Título revista:Brain, Behavior, and Immunity
Título revista abreviado:Brain Behav. Immun.
CAS:RNA, Messenger; Transforming Growth Factor beta1


  • Ageta, H., Murayama, A., Migishima, R., Kida, S., Tsuchida, K., Yokoyama, M., Inokuchi, K., Activin in the brain modulates anxiety-related behavior and adult neurogenesis (2008) PLoS ONE, 3, pp. e1869
  • Ansorge, M.S., Zhou, M., Lira, A., Hen, R., Gingrich, J.A., Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice (2004) Science, 306, pp. 879-881
  • Ashwood, P., Enstrom, A., Krakowiak, P., Hertz-Picciotto, I., Hansen, R.L., Croen, L.A., Ozonoff, S., Van de Water, J., Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes (2008) J. Neuroimmunol., 204, pp. 149-153
  • (2000) Diagnostic and Statistical Manual of Mental Disorders, Text Revision, , American Psychiatric Association, American Psychiatric Association, Washington, DC
  • Battista, D., Ferrari, C.C., Gage, F.H., Pitossi, F.J., Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus (2006) Eur. J. Neurosci., 23, pp. 83-93
  • Benes, F.M., Lim, B., Matzilevich, D., Walsh, J.P., Subburaju, S., Minns, M., Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars (2007) Proc. Natl. Acad. Sci. USA, 104, pp. 10164-10169
  • Blond, D., Campbell, S.J., Butchart, A.G., Perry, V.H., Anthony, D.C., Differential induction of interleukin-1beta and tumour necrosis factor-alpha may account for specific patterns of leukocyte recruitment in the brain (2002) Brain Res., 958, pp. 89-99
  • Boisse, L., Mouihate, A., Ellis, S., Pittman, Q.J., Long-term alterations in neuroimmune responses after neonatal exposure to lipopolysaccharide (2004) J. Neurosci., 24, pp. 4928-4934
  • Bottner, M., Krieglstein, K., Unsicker, K., The transforming growth factor-betas: structure, signaling, and roles in nervous system development and functions (2000) J. Neurochem., 75, pp. 2227-2240
  • Brodkin, E.S., Hagemann, A., Nemetski, S.M., Silver, L.M., Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice (2004) Brain Res., 1002, pp. 151-157
  • Casanova, M., Trippe, J., Radial cytoarchitecture and patterns of cortical connectivity in autism (2009) Philos. Trans. R. Soc. B: Biol. Sci., 364, pp. 1433-1436
  • Crawley, J.N., Mouse behavioral assays relevant to the symptoms of autism (2007) Brain Pathol. (Zurich, Switzerland), 17, pp. 448-459
  • Cunningham, C., Boche, D., Perry, V.H., Transforming growth factor beta1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix (2002) Neuropathol. Appl. Neurobiol., 28, pp. 107-119
  • Depino, A., Ferrari, C., Pott Godoy, M.C., Tarelli, R., Pitossi, F.J., Differential effects of interleukin-1beta on neurotoxicity, cytokine induction and glial reaction in specific brain regions (2005) J. Neuroimmunol., 168, pp. 96-110
  • Depino, A.M., Tsetsenis, T., Gross, C., GABA homeostasis contributes to the developmental programming of anxiety-related behavior (2008) Brain Res., 1210, pp. 189-199
  • Deverman, B.E., Patterson, P.H., Cytokines and CNS development (2009) Neuron, 64, pp. 61-78
  • Dow, A.L., Russell, D.S., Duman, R.S., Regulation of activin mRNA and Smad2 phosphorylation by antidepressant treatment in the rat brain: effects in behavioral models (2005) J. Neurosci., 25, pp. 4908-4916
  • Fatemi, S.H., Snow, A.V., Stary, J.M., Araghi-Niknam, M., Reutiman, T.J., Lee, S., Brooks, A.I., Pearce, D.A., Reelin signaling is impaired in autism (2005) Biol. Psychiatry, 57, pp. 777-787
  • Ferrari, C.C., Depino, A.M., Prada, F., Muraro, N., Campbell, S., Podhajcer, O., Perry, V.H., Pitossi, F.J., Reversible demyelination, blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain (2004) Am. J. Pathol., 165, pp. 1827-1837
  • Forster, E., Tielsch, A., Saum, B., Weiss, K.H., Johanssen, C., Graus-Porta, D., Muller, U., Frotscher, M., Reelin, Disabled 1, and beta 1 integrins are required for the formation of the radial glial scaffold in the hippocampus (2002) Proc. Natl. Acad. Sci. USA, 99, pp. 13178-13183
  • Garbett, K., Ebert, P.J., Mitchell, A., Lintas, C., Manzi, B., Mirnics, K., Persico, A.M., Immune transcriptome alterations in the temporal cortex of subjects with autism (2008) Neurobiol. Dis., 30, pp. 303-311
  • Gomes, F.C., Sousa Vde, O., Romao, L., Emerging roles for TGF-beta1 in nervous system development (2005) Int. J. Dev. Neurosci., 23, pp. 413-424
  • Graciarena, M., Depino, A.M., Pitossi, F.J., Prenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFbeta(1) downregulation (2010) Brain Behav. Immun., 24, pp. 1301-1309
  • Greco, C.M., Navarro, C.S., Hunsaker, M.R., Maezawa, I., Shuler, J.F., Tassone, F., Delany, M., Hagerman, R.J., Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome (2011) Mol. Autism, 2, p. 2
  • Gross, C., Zhuang, X., Stark, K., Ramboz, S., Oosting, R., Kirby, L., Santarelli, L., Hen, R., Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult (2002) Nature, 416, pp. 396-400
  • Hofvander, B., Delorme, R., Chaste, P., Nyden, A., Wentz, E., Stahlberg, O., Herbrecht, E., Leboyer, M., Psychiatric and psychosocial problems in adults with normal-intelligence autism spectrum disorders (2009) BMC Psychiatry, 9, p. 35
  • Ichtchenko, K., Nguyen, T., Sudhof, T.C., Structures, alternative splicing, and neurexin binding of multiple neuroligins (1996) J. Biol. Chem., 271, pp. 2676-2682
  • Khazipov, R., Luhmann, H.J., Early patterns of electrical activity in the developing cerebral cortex of humans and rodents (2006) Trends Neurosci., 29, pp. 414-418
  • Kolozsi, E., Mackenzie, R.N., Roullet, F.I., deCatanzaro, D., Foster, J.A., Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice (2009) Neuroscience, 163, pp. 1201-1210
  • Kulkarni, A.B., Huh, C.G., Becker, D., Geiser, A., Lyght, M., Flanders, K.C., Roberts, A.B., Karlsson, S., Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death (1993) Proc. Natl. Acad. Sci. USA, 90, pp. 770-774
  • Laumonnier, F., Bonnet-Brilhault, F., Gomot, M., Blanc, R., David, A., Moizard, M.P., Raynaud, M., Briault, S., X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family (2004) Am. J. Hum. Genet., 74, pp. 552-557
  • Lawrence, Y.A., Kemper, T.L., Bauman, M.L., Blatt, G.J., Parvalbumin-, calbindin-, and calretinin-immunoreactive hippocampal interneuron density in autism (2010) Acta Neurol. Scand., 121, pp. 99-108
  • Lintas, C., Sacco, R., Persico, A.M., (2011), Genome-wide expression studies in Autism spectrum disorder, Rett syndrome, and Down syndrome. Neurobiol. Dis; Lucchina, L., Carola, V., Pitossi, F., Depino, A.M., Evaluating the interaction between early postnatal inflammation and maternal care in the programming of adult anxiety and depression-related behaviors (2010) Behav. Brain Res., 213, pp. 56-65
  • Magdaleno, S., Jensen, P., Brumwell, C.L., Seal, A., Lehman, K., Asbury, A., Cheung, T., Curran, T., BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system (2006) PLoS Biol., 4, pp. e86
  • McFarlane, H.G., Kusek, G.K., Yang, M., Phoenix, J.L., Bolivar, V.J., Crawley, J.N., Autism-like behavioral phenotypes in BTBR T+tf/J mice (2008) Genes Brain Behav., 7, pp. 152-163
  • Meyer, U., Nyffeler, M., Engler, A., Urwyler, A., Schedlowski, M., Knuesel, I., Yee, B.K., Feldon, J., The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology (2006) J. Neurosci., 26, pp. 4752-4762
  • Okada, K., Hashimoto, K., Iwata, Y., Nakamura, K., Tsujii, M., Tsuchiya, K.J., Sekine, Y., Mori, N., Decreased serum levels of transforming growth factor-beta1 in patients with autism (2007) Prog. Neuropsychopharmacol. Biol. Psychiatry, 31, pp. 187-190
  • Patterson, P.H., (2011), Maternal infection and immune involvement in autism. Trends Mol. Med; Paxinos, G., Watson, C., (1986) The Rat Brain in Stereotaxic Coordinates, , Academic Press, Orlando, FL
  • Persico, A.M., D'Agruma, L., Maiorano, N., Totaro, A., Militerni, R., Bravaccio, C., Wassink, T.H., Keller, F., Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder (2001) Mol. Psychiatry, 6, pp. 150-159
  • Pierce, K., Courchesne, E., Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism (2001) Biol. Psychiatry, 49, pp. 655-664
  • Radyushkin, K., Hammerschmidt, K., Boretius, S., Varoqueaux, F., El-Kordi, A., Ronnenberg, A., Winter, D., Ehrenreich, H., (2009), Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav; Rasband, W.S., 1997-2009. ImageJ. In: Health, N.I.O. (Ed.), Bethesda; Saitoh, O., Karns, C.M., Courchesne, E., Development of the hippocampal formation from 2 to 42 years: MRI evidence of smaller area dentata in autism (2001) Brain, 124, pp. 1317-1324
  • Schneider, T., Roman, A., Basta-Kaim, A., Kubera, M., Budziszewska, B., Schneider, K., Przewlocki, R., Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid (2008) PNEC, 33, pp. 728-740
  • Smith, S.E., Li, J., Garbett, K., Mirnics, K., Patterson, P.H., Maternal immune activation alters fetal brain development through interleukin-6 (2007) J. Neurosci., 27, pp. 10695-10702
  • Sun, M., Gewirtz, J.C., Bofenkamp, L., Wickham, R.J., Ge, H., O'Connor, M.B., Canonical TGF-beta signaling is required for the balance of excitatory/inhibitory transmission within the hippocampus and prepulse inhibition of acoustic startle (2010) J. Neurosci., 30, pp. 6025-6035
  • Vargas, D.L., Nascimbene, C., Krishnan, C., Zimmerman, A.W., Pardo, C.A., Neuroglial activation and neuroinflammation in the brain of patients with autism (2005) Ann. Neurol., 57, pp. 67-81
  • Weeber, E.J., Beffert, U., Jones, C., Christian, J.M., Forster, E., Sweatt, J.D., Herz, J., Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning (2002) J. Biol. Chem., 277, pp. 39944-39952
  • Wegiel, J., Kuchna, I., Nowicki, K., Imaki, H., Marchi, E., Ma, S.Y., Chauhan, A., Wisniewski, T., The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes (2010) Acta Neuropathol., 119, pp. 755-770
  • Weiss, J.M., Cuff, C.A., Berman, J.W., TGF-beta downmodulates cytokine-induced monocyte chemoattractant protein (MCP)-1 expression in human endothelial cells. A putative role for TGF-beta in the modulation of TNF receptor expression (1999) Endothelium, 6, pp. 291-302
  • Wyss-Coray, T., Borrow, P., Brooker, M.J., Mucke, L., Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice (1997) J. Neuroimmunol., 77, pp. 45-50
  • Zhang, H., Liu, X., Zhang, C., Mundo, E., Macciardi, F., Grayson, D.R., Guidotti, A.R., Holden, J.J., Reelin gene alleles and susceptibility to autism spectrum disorders (2002) Mol. Psychiatry, 7, pp. 1012-1017
  • Zheng, F., Adelsberger, H., Muller, M.R., Fritschy, J.M., Werner, S., Alzheimer, C., Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior (2009) Mol. Psychiatry, 14, pp. 332-346


---------- APA ----------
Depino, A.M., Lucchina, L. & Pitossi, F. (2011) . Early and adult hippocampal TGF-β1 overexpression have opposite effects on behavior. Brain, Behavior, and Immunity, 25(8), 1582-1591.
---------- CHICAGO ----------
Depino, A.M., Lucchina, L., Pitossi, F. "Early and adult hippocampal TGF-β1 overexpression have opposite effects on behavior" . Brain, Behavior, and Immunity 25, no. 8 (2011) : 1582-1591.
---------- MLA ----------
Depino, A.M., Lucchina, L., Pitossi, F. "Early and adult hippocampal TGF-β1 overexpression have opposite effects on behavior" . Brain, Behavior, and Immunity, vol. 25, no. 8, 2011, pp. 1582-1591.
---------- VANCOUVER ----------
Depino, A.M., Lucchina, L., Pitossi, F. Early and adult hippocampal TGF-β1 overexpression have opposite effects on behavior. Brain Behav. Immun. 2011;25(8):1582-1591.