Disrupted Timing of MET Signaling Derails the Developmental Maturation of Cortical Circuits and Leads to Altered Behavior in Mice

Xiaokuang Ma, Jing Wei, Yuehua Cui, Baomei Xia, Le Zhang, Antoine Nehme, Yi Zuo, Deveroux Ferguson, Pat Levitt, Shenfeng Qiu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The molecular regulation of the temporal dynamics of circuit maturation is a key contributor to the emergence of normal structure-function relations. Developmental control of cortical MET receptor tyrosine kinase, expressed early postnatally in subpopulations of excitatory neurons, has a pronounced impact on the timing of glutamatergic synapse maturation and critical period plasticity. Here, we show that using a controllable overexpression (cto-Met) transgenic mouse, extending the duration of MET signaling after endogenous Met is switched off leads to altered molecular constitution of synaptic proteins, persistent activation of small GTPases Cdc42 and Rac1, and sustained inhibitory phosphorylation of cofilin. These molecular changes are accompanied by an increase in the density of immature dendritic spines, impaired cortical circuit maturation of prefrontal cortex layer 5 projection neurons, and altered laminar excitatory connectivity. Two photon in vivo imaging of dendritic spines reveals that cto-Met enhances de novo spine formation while inhibiting spine elimination. Extending MET signaling for two weeks in developing cortical circuits leads to pronounced repetitive activity and impaired social interactions in adult mice. Collectively, our data revealed that temporally controlled MET signaling as a critical mechanism for controlling cortical circuit development and emergence of normal behavior.

Original languageEnglish (US)
Pages (from-to)1769-1786
Number of pages18
JournalCerebral Cortex
Volume32
Issue number8
DOIs
StatePublished - Apr 15 2022

Keywords

  • autism
  • circuit connectivity
  • cortical circuits
  • molecular mechanisms
  • neurodevelopmental disorders
  • plasticity
  • synapses

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Disrupted Timing of MET Signaling Derails the Developmental Maturation of Cortical Circuits and Leads to Altered Behavior in Mice'. Together they form a unique fingerprint.

Cite this