Lack of serotonin transporter alters BDNF expression in the rat brain during early postnatal development

Mol Neurobiol. 2013 Aug;48(1):244-56. doi: 10.1007/s12035-013-8449-z. Epub 2013 Apr 9.

Abstract

It is well established that alterations of the serotoninergic system may contribute to the pathophysiology of mood disorders. Accordingly, it has been demonstrated that genetic deletion of the serotonin transporter (SERT) in rodents leads to an anxious and depressive phenotype, which is also associated with reduced neuronal plasticity. Indeed, we have demonstrated that adult SERT(-/-) animals show decreased brain-derived neurotrophic factor (BDNF) expression, as well as reduced levels of transcription factor regulating the neurotrophin transcription. While these changes may represent long-term consequences of impaired function of the transporter during development, no information exists with respect to the developmental profile of such changes. Using SERT(-/-) rats at different ages, we found that the impairment in neuroplasticity originates early in development and worsens during the first 3 weeks of life. Indeed, we observed that BDNF expression was reduced at birth and that the magnitude of these changes became more pronounced starting from PND21, being sustained by epigenetic mechanisms as well as alterations in the expression of specific transcription factors, including Npas4 and CaRF. These results suggest that an impairment of SERT may affect BDNF expression throughout postnatal development. These early changes may increase stress susceptibility during critical windows of brain maturation, which may eventually lead to the heightened predisposition to mood disorders found in individual carrying genetic variants of the serotonin transporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain / growth & development*
  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / genetics*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / genetics
  • Exons / genetics
  • Gene Expression Regulation, Developmental*
  • Hippocampus / growth & development
  • Hippocampus / metabolism
  • Male
  • Prefrontal Cortex / growth & development
  • Prefrontal Cortex / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Serotonin Plasma Membrane Transport Proteins / deficiency
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Antigens, Differentiation
  • Basic Helix-Loop-Helix Transcription Factors
  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • Gadd45b protein, rat
  • Npas4 protein, rat
  • Protein Isoforms
  • RNA, Messenger
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, rat
  • Transcription Factors
  • calcium response transcription factor 1, rat
  • gamma-Aminobutyric Acid
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases