The MeCP2-null mouse hippocampus displays altered basal inhibitory rhythms and is prone to hyperexcitability

Hippocampus. 2008;18(3):294-309. doi: 10.1002/hipo.20389.

Abstract

Rett syndrome is an autism-spectrum disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2). While subtle decreases in synaptic plasticity have been detected within cortical and hippocampal neurons of Mecp2-null mice, only minimal information exists regarding how the loss of MeCP2 affects network activity in the brain. To address this issue, we compared the intrinsic network activities of Mecp2-null hippocampal slices derived from symptomatic mice to wild-type slices. Extracellular and whole-cell patch recordings revealed that although spontaneous, IPSP-based rhythmic activity is present in Mecp2-null slices; its frequency is significantly reduced from wild-type. This reduction was not associated with alterations in the gross electrophysiological properties of hippocampal neurons, but was associated with a decreased level of spontaneous glutamate receptor-mediated synaptic currents in hippocampal CA3 neurons. Paradoxically, however, repetitive sharp wave-like discharges were readily induced in the Mecp2-null hippocampal slices by a brief train of high-frequency stimulation commonly used to establish long-term potentiation at wild-type slices. Taken together, our data indicate that the Mecp2-null hippocampal CA3 circuit has diminished basal inhibitory rhythmic activity, which in turn renders the circuitry prone to hyperexcitability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / genetics*
  • Animals
  • Biological Clocks / physiology*
  • Cortical Synchronization
  • DNA-Binding Proteins / genetics
  • Electric Stimulation
  • Female
  • Glutamic Acid / metabolism
  • Hippocampus / metabolism
  • Hippocampus / physiopathology*
  • Inhibitory Postsynaptic Potentials / genetics
  • Long-Term Potentiation / genetics
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mice
  • Mice, Knockout
  • Nerve Net / metabolism
  • Nerve Net / physiopathology*
  • Neural Inhibition / genetics*
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Periodicity
  • Rett Syndrome / genetics
  • Rett Syndrome / metabolism
  • Rett Syndrome / physiopathology
  • Synaptic Transmission / genetics

Substances

  • DNA-Binding Proteins
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Glutamic Acid