Disrupted Timing of MET Signaling Derails the Developmental Maturation of Cortical Circuits and Leads to Altered Behavior in Mice
| Autor: | Deveroux Ferguson, Yuehua Cui, Jing Wei, Pat Levitt, Xiaokuang Ma, Le Zhang, Baomei Xia, Antoine Nehme, Shenfeng Qiu, Yi Zuo |
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| Rok vydání: | 2022 |
| Předmět: |
Genetically modified mouse
Dendritic spine Cognitive Neuroscience Dendritic Spines Neurogenesis 1.1 Normal biological development and functioning molecular mechanisms autism Biology Inhibitory postsynaptic potential Inbred C57BL Cellular and Molecular Neuroscience Mice Underpinning research Animals Psychology Prefrontal cortex Neurons Developmental maturation cortical circuits Critical Period Psychological neurodevelopmental disorders Neurosciences Experimental Psychology Cofilin Mice Inbred C57BL plasticity Synapses Neurological Excitatory postsynaptic potential Critical Period Psychological Original Article Cognitive Sciences Glutamatergic synapse Neuroscience circuit connectivity |
| Zdroj: | Cerebral cortex (New York, N.Y. : 1991), vol 32, iss 8 Cereb Cortex |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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