Abstract
Normal development of cortical circuits, including experience-dependent cortical maturation and plasticity, requires precise temporal regulation of gene expression and molecular signaling. Such regulation, and the concomitant impact on plasticity and critical periods, is hypothesized to be disrupted in neurodevelopmental disorders. A protein that may serve such a function is the MET receptor tyrosine kinase, which is tightly regulated developmentally in rodents and primates, and exhibits reduced cortical expression in autism spectrum disorder and Rett Syndrome. We found that the peak of MET expression in developing mouse cortex coincides with the heightened period of synaptogenesis, but is precipitously downregulated prior to extensive synapse pruning and certain peak periods of cortical plasticity. These results reflect a potential on–off regulatory synaptic mechanism for specific glutamatergic cortical circuits in which MET is enriched. In order to address the functional significance of the ‘off’ component of the proposed mechanism, we created a controllable transgenic mouse line that sustains cortical MET signaling. Continued MET expression in cortical excitatory neurons disrupted synaptic protein profiles, altered neuronal morphology, and impaired visual cortex circuit maturation and connectivity. Remarkably, sustained MET signaling eliminates monocular deprivation-induced ocular dominance plasticity during the normal cortical critical period; while ablating MET signaling leads to early closure of critical period plasticity. The results demonstrate a novel mechanism in which temporal regulation of a pleiotropic signaling protein underlies cortical circuit maturation and timing of cortical critical period, features that may be disrupted in neurodevelopmental disorders.
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Acknowledgements
This study was supported by NIH/NIMH grants R01MH111619 (SQ) and R01MH067842 (PL), the Simms/Mann Chair in Developmental Neurogenetics and the WM Keck Chair in Neurogenetics (PL), and institution startup fund from the University of Arizona (SQ). We would like to thank A.W. McGee (University of Louisville) for his assistance in developing the experimental design for measuring ocular dominance plasticity, as well as helpful discussion of these experiments.
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KC, XM performed the majority of experiments. KC, Yan C, Yuehua C, and DY developed OD plasticity data collection and analysis methods. AN, JW, TA, DF, SQ contributed to data collection and analyses. PL and SQ designed the experiments, supervised the work and wrote the paper.
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Chen, K., Ma, X., Nehme, A. et al. Time-delimited signaling of MET receptor tyrosine kinase regulates cortical circuit development and critical period plasticity. Mol Psychiatry 26, 3723–3736 (2021). https://doi.org/10.1038/s41380-019-0635-6
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DOI: https://doi.org/10.1038/s41380-019-0635-6
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