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The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression.

Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MeCP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in Mecp2 mutant mice, and deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the Mecp2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in Mecp2 mutants. Our results provide in vivo evidence for a functional interaction between Mecp2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.

Pubmed ID: 16446138

Authors

  • Chang Q
  • Khare G
  • Dani V
  • Nelson S
  • Jaenisch R

Journal

Neuron

Publication Data

February 2, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA087869

Mesh Terms

  • Action Potentials
  • Animals
  • Animals, Newborn
  • Behavior, Animal
  • Brain
  • Brain-Derived Neurotrophic Factor
  • Disease Models, Animal
  • Disease Progression
  • Electric Stimulation
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Male
  • Methyl-CpG-Binding Protein 2
  • Mice
  • Mice, Knockout
  • Motor Activity
  • Mutation
  • Neurons
  • Organ Size
  • Patch-Clamp Techniques
  • RNA, Messenger
  • Rett Syndrome
  • Reverse Transcriptase Polymerase Chain Reaction