Electrophysiological phenotypes of MeCP2 A140V mutant mouse model

Lu Yao Ma, Chen Wu, Yu Jin, Ming Gao, Guo Hui Li, Dharshaun Turner, Jian Xin Shen, Shi Jiang Zhang, Vinodh Narayanan, Garilyn Jentarra, Jie Wu

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Aims: MeCP2 gene mutations are associated with Rett syndrome and X-linked mental retardation (XLMR), diseases characterized by abnormal brain development and function. Recently, we created a novel MeCP2 A140V mutation mouse model that exhibited abnormalities of cell packing density and dendritic branching consistent with that seen in Rett syndrome patients as well as other MeCP2 mutant mouse models. Therefore, we hypothesized that some deficits of neuronal and synaptic functions might also be present in the A140V mutant model. Methods: Here, we tested our hypothesis in hippocampal slices using electrophysiological recordings. Results: We found that in young A140V mutant mice (3- to 4-week-old), hippocampal CA1 pyramidal neurons exhibited more positive resting membrane potential, increased action potential (AP) firing frequency induced by injection of depolarizing current, wider AP duration, and smaller after hyperpolarization potential compared to neurons prepared from age-matched wild-type mice, suggesting a neuronal hyperexcitation. At the synaptic level, A140V mutant neurons exhibited a reduced frequency of spontaneous IPSCs (inhibitory postsynaptic potentials) and an enhanced probability of evoked glutamate release, both suggesting neuronal hyperexcitation. However, hippocampal CA1 long-term potentiation was not significantly different between A140V and WT mice. In adult mice (11- to 13-month-old), in addition to neuronal hyperexcitation, we also found significant deficits of both short-term and long-term potentiation of CA3-CA1 synapses in A140V mice compared to WT mice. Conclusions: These results clearly illustrate the age-dependent abnormalities of neuronal and synaptic function in the MeCP2 A140V mutant mouse model, which provides new insights into the understanding of the pathogenesis of Rett syndrome.

Original languageEnglish (US)
Pages (from-to)420-428
Number of pages9
JournalCNS Neuroscience and Therapeutics
Volume20
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • Electrophysiology
  • Hippocampal slice
  • Long-term potentiation
  • MeCP2 gene
  • Rett model
  • Synaptic transmission

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)

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