Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment

J Neurosci. 2012 Oct 3;32(40):13860-72. doi: 10.1523/JNEUROSCI.2159-12.2012.

Abstract

Excitatory-inhibitory imbalance has been identified within specific brain microcircuits in models of Rett syndrome (RTT) and other autism spectrum disorders (ASDs). However, macrocircuit dysfunction across the RTT brain as a whole has not been defined. To approach this issue, we mapped expression of the activity-dependent, immediate-early gene product Fos in the brains of wild-type (Wt) and methyl-CpG-binding protein 2 (Mecp2)-null (Null) mice, a model of RTT, before and after the appearance of overt symptoms (3 and 6 weeks of age, respectively). At 6 weeks, Null mice exhibit significantly less Fos labeling than Wt in limbic cortices and subcortical structures, including key nodes in the default mode network. In contrast, Null mice exhibit significantly more Fos labeling than Wt in the hindbrain, most notably in cardiorespiratory regions of the nucleus tractus solitarius (nTS). Using nTS as a model, whole-cell recordings demonstrated that increased Fos expression in Nulls at 6 weeks of age is associated with synaptic hyperexcitability, including increased frequency of spontaneous and miniature EPSCs and increased amplitude of evoked EPSCs in Nulls. No such effect of genotype on Fos or synaptic function was seen at 3 weeks. In the mutant forebrain, reduced Fos expression, as well as abnormal sensorimotor function, were reversed by the NMDA receptor antagonist ketamine. In light of recent findings that the default mode network is hypoactive in autism, our data raise the possibility that hypofunction within this meta-circuit is a shared feature of RTT and other ASDs and is reversible.

Publication types

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

MeSH terms

  • Animals
  • Autonomic Nervous System / physiopathology*
  • Cerebellum / metabolism
  • Cerebellum / physiopathology
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Gene Expression Regulation, Developmental
  • Genes, fos
  • Humans
  • Ketamine / pharmacology*
  • Male
  • Methyl-CpG-Binding Protein 2 / deficiency
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / physiology*
  • Mice
  • Mice, Knockout
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / physiology
  • Nerve Net / drug effects
  • Nerve Net / metabolism
  • Nerve Net / physiopathology*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Organ Specificity
  • Patch-Clamp Techniques
  • Prosencephalon / metabolism
  • Prosencephalon / physiopathology*
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Rett Syndrome / genetics
  • Rett Syndrome / physiopathology
  • Sensory Gating / drug effects
  • Sensory Gating / physiology
  • Solitary Nucleus / chemistry
  • Solitary Nucleus / metabolism
  • Solitary Nucleus / physiopathology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Excitatory Amino Acid Antagonists
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • Ketamine