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PLC-β1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex

Abstract

During development of the cerebral cortex, the invasion of thalamic axons and subsequent differentiation of cortical neurons are tightly coordinated. Here we provide evidence that glutamate neurotransmission triggers a critical signaling mechanism involving the activation of phospholipase C-β1 (PLC-β1) by metabotropic glutamate receptors (mGluRs). Homozygous null mutation of either PLC-β1 or mGluR5 dramatically disrupts the cytoarchitectural differentiation of 'barrels' in the mouse somatosensory cortex, despite segregation in the pattern of thalamic innervation. Furthermore, group 1 mGluR-stimulated phosphoinositide hydrolysis is dramatically reduced in PLC-β1−/− mice during barrel development. Our data indicate that PLC-β1 activation via mGluR5 is critical for the coordinated development of the neocortex, and that presynaptic and postsynaptic components of cortical differentiation can be genetically dissociated.

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Figure 1: Failure of cortical barrel formation in PLC-β1−/− mice.
Figure 2: Thalamocortical axons segregate into a barrel pattern in PLC-β1−/− mice.
Figure 3: Despite partial thalamocortical segregation, mGluR5−/− mice fail to form normal cortical barrels.
Figure 4: Lithium chloride-amplified agonist-induced inositol phosphate (IP) generation from cortical synaptoneurosome preparations at one week and over three weeks of age.

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Acknowledgements

This work was supported by the Medical Research Council (C.B.), the Wellcome Trust (P.K., C.B.) the Nuffield Medical Trust (A.H.), Oxford McDonnell-Pew Centre for Cognitive Neuroscience and a Creative Research Initiative Program from the Korean Government (H.S.). We thank T. Andrews, A. van Dellen, Z. Molnar, D. Moore and C. Hannan for discussions and comments on earlier versions of the manuscript, and M. O'Brien and P. Cordery for technical assistance.

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Correspondence to Peter C. Kind.

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Hannan, A., Blakemore, C., Katsnelson, A. et al. PLC-β1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex. Nat Neurosci 4, 282–288 (2001). https://doi.org/10.1038/85132

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