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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.

Miriam Kron, C James Howell, Ian T Adams, Michael Ransbottom, Diana Christian, Michael Ogier, David M Katz

Journal of Neuroscience October 3, 2012 DOI: 10.1523/jneurosci.2159-12.2012 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Animal experimental study Peer reviewed
Population Wild-type and Mecp2-null mice, a model of Rett syndrome, at 3 and 6 weeks of age
Intervention Ketamine
Measures Fos labeling, whole-cell recordings of spontaneous and miniature EPSCs and evoked EPSCs, sensorimotor function
Topics Default mode network Esketamine Ketamine
Key findings At 6 weeks, Mecp2-null mice showed less Fos labeling than wild-type mice in limbic cortices and subcortical structures, including default mode network nodes, but more Fos labeling in hindbrain cardiorespiratory regions such as the nucleus tractus solitarius, where increased Fos was associated with synaptic hyperexcitability. No genotype differences were seen at 3 weeks. Ketamine reversed reduced forebrain Fos and abnormal sensorimotor function. The authors propose that default mode network hypofunction may be a shared, reversible feature of Rett syndrome and other autism spectrum disorders.

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.

Comparable studies

Other preclinical and animal studies on default mode network, most cited first.

Study Year Design Participants
Rat brains also have a default mode network Rats 2012 Observational study
Large-scale topology and the default mode network in the mouse connectome Mouse brain 2014 Observational study
Hippocampal Sharp-Wave Ripples Influence Selective Activation of the Default Mode Network Anesthetized monkeys 2016 Observational study
Psilocybin-induced default mode network hypoconnectivity is blunted in alcohol-dependent rats Healthy rats and a rat model of alcohol relapse 2023 Randomized, placebo-controlled crossover pharmaco-fMRI study
Altered functional connectivity within the default mode network in two animal models with opposing episodic memories Rats (control, LPS-challenged, and footshock-exposed groups) 2018 Animal model study

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Default mode network Esketamine Ketamine Addiction