title: 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.
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.
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kron
authors.forename: C James
authors.initials: CJ
authors.lastname: Howell
authors.forename: Ian T
authors.initials: IT
authors.lastname: Adams
authors.forename: Michael
authors.initials: M
authors.lastname: Ransbottom
authors.forename: Diana
authors.initials: D
authors.lastname: Christian
authors.forename: Michael
authors.initials: M
authors.lastname: Ogier
authors.forename: David M
authors.initials: DM
authors.lastname: Katz
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000503:physiopathology*; D002531:Cerebellum / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016762:Genes, fos; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009928:Organ Specificity; D018408:Patch-Clamp Techniques; D016548:Prosencephalon / Q000378:metabolism / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D015518:Rett Syndrome / Q000235:genetics / Q000503:physiopathology; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology; D017552:Solitary Nucleus / Q000737:chemistry / Q000378:metabolism / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D007649:Ketamine