Loss of MeCP2 in immature neurons leads to impaired network integration

Hum Mol Genet. 2019 Jan 15;28(2):245-257. doi: 10.1093/hmg/ddy338.


Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations or deletions in Methyl-CpG-binding Protein 2 (MeCP2), a brain-enriched transcriptional regulator. MeCP2 is highly expressed during neuronal maturation and its deficiency results in impaired dendritic morphogenesis and reduced dendritic spine numbers in developing neurons. However, whether MeCP2 deficiency impacts the integration of new neurons has not been directly assessed. In this study, we developed a modified rabies virus-mediated monosynaptic retrograde tracing method to interrogate presynaptic integration of MeCP2-deficient new neurons born in the adult hippocampus, a region with lifelong neurogenesis and plasticity. We found that selective deletion of MeCP2 in adult-born new neurons impaired their long-range connectivity to the cortex, whereas their connectivity within the local hippocampal circuits or with subcortical regions was not significantly affected. We further showed that knockdown of MeCP2 in primary hippocampal neurons also resulted in reduced network integration. Interestingly, (1-3) insulin-like growth factor-1 (IGF-1), a small peptide under clinical trial testing for RTT, rescued neuronal integration deficits of MeCP2-deficient neurons in vitro but not in vivo. In addition, (1-3) IGF-1 treatment corrected aberrant excitability and network synchrony of MeCP2-deficient hippocampal neurons. Our results indicate that MeCP2 is essential for immature neurons to establish appropriate network connectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendrites
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Insulin-Like Growth Factor I / pharmacology
  • Male
  • Methyl-CpG-Binding Protein 2 / deficiency
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Nerve Net*
  • Neuroanatomical Tract-Tracing Techniques
  • Neurogenesis* / drug effects
  • Neurons / cytology*
  • Neurons / metabolism
  • Retroviridae


  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Insulin-Like Growth Factor I