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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Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1139 (1996).
Woolsey, D. H. & Van der Loos, H. The structural organization of layer IV in the somatosensory region (SI) of the mouse cerebral cortex. Brain Res. 17, 205–242 (1970).
Woolsey, T. A., Dierker, M. L. & Wann, D. F. Mouse SmI cortex: qualitative and quantitative classification of golgi-impregnated barrel neurons. Proc. Natl. Acad. Sci. USA 72, 2165–2169 (1975).
Killackey, H. P. & Belford, G. R. The formation of afferent patterns in the somatosensory cortex of the neonatal rat. J. Comp. Neurol. 183, 285–304 (1979).
O'Leary, D. D. M., Ruff, N. L. & Dyck, R. H. Development, critical period plasticity, and adult reorganizations of mammalian somatosensory systems. Curr. Opin. Neurobiol. 4, 535–544 (1994).
Agmon, A., Yang, L. T., Jones, E. G. & O'Dowd, D. K. Topological precision in the thalamic projection to neonatal mouse barrel cortex. J. Neurosci. 15, 549–561 (1995).
Van der Loos, H. & Woolsey, T. A. Somatosensory cortex: structural alterations following early injury to sense organs. Science 179, 395–398 (1973).
Greenough, W. T. & Chang, F.-L. F. Dendritic pattern formation involves both oriented regression and oriented growth of barrels of mouse somatosensory cortex. Brain Res. Dev. Brain Res. 43, 148–152 (1988).
Schlaggar, B. L. & O'Leary D. D. Potential of visual cortex to develop an array of functional units unique to somatosensory cortex. Science 252, 1556–1560 (1991).
Welker, E. et al. Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless. Science 271, 1864–1867 (1996).
Abdel-Majid, R. M. et al. Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nat. Genet. 19, 289–291 (1998).
Cases, O. et al. Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 16, 297–307 (1996).
Kind, P. C., Blakemore, C., Fryer, H. & Hockfield, S. Identification of proteins downregulated during the postnatal development of the cat visual cortex. Cereb. Cortex 4, 361–375 (1994).
Kind, P. C., Kelly, G. M., Fryer, H. J. L., Blakemore, C. & Hockfield, S. Phospholipase C-β1 is present in the botrysome, an intermediate compartment-like organelle, and is regulated by visual experience in cat visual cortex. J. Neurosci. 17, 1471–1480 (1997).
Hannan, A. J., Kind, P. C. & Blakemore, C. Phospholipase C-β1 expression correlates with neuronal differentiation and synaptic plasticity in rat somatosensory cortex. Neuropharmacology 37, 593–605 (1998).
De Camilli, P., Emr, S. D., McPherson, P. S. & Novick, P. Phosphoinositides as regulators in membrane traffic. Science 271, 1533–1539 (1996).
Fabbri, M., Bannykh, S. & Balch W. E. Export of protein from the endoplasmic reticulum is regulated by a diacylglycerol/phorbol ester binding protein. J. Biol. Chem. 269, 26848–26857 (1994).
Bevilacqua, J. A., Downes, C. P. & Lowenstein, P. R. Transiently selective activation of phosphoinositide turnover in layer V pyramidal neurons after specific mGluRs stimulation in rat somatosensory cortex during early postnatal development. J. Neurosci. 15, 7916–7928 (1995).
Dudek, S. & Bear, M. F. A biochemical correlate of the critical period for synaptic modification in the visual cortex. Science 246, 673–675 (1989).
Reid, S. N. M., Romano, C., Hughes, T. & Daw, N. W. Immunohistochemical study of two phosphoinositide-linked metabotropic glutamate receptors (mGluR1a and mGluR5) in the cat visual cortex before, during and after the peak of the critical period for eye-specific connections. J. Comp. Neurol. 355, 470–477 (1995).
Blue, M. E., Martin, L. J., Brennan, E. M. & Johnston, M. V. Ontogeny of non-NMDA glutamate receptors in rat barrel field cortex: I. Metabotropic receptors. J. Comp. Neurol. 386, 16–28 (1997).
Munoz, A., Liu, X. B. & Jones, E. G. Development of metabotropic glutamate receptors from trigeminal nuclei to barrel cortex in postnatal mouse. J. Comp. Neurol. 409, 549–566 (1999).
Kim, D. et al. Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389, 290–293 (1997).
Lu, Y.-M. et al. Mice lacking mGluR5 show impaired learning and reduced CA1 LTP, but normal CA3 LTP. J. Neurosci. 17, 5196–5205 (1997).
Jia, Z. et al. Selective abolition of the NMDA component of long term potentiation in mice lacking mGluR5. Learn. Mem. 5, 331–343 (1998).
Huber, K. M. Kayser, M. S. & Bear, M. F. Role for rapid dendritic protein synthesis in hippocampal homosynaptic long-term depression. Science 288, 1254–1257 (2000).
Fitzjohn, S. M., Kingston, A. E., Lodge, D. & Collingridge, G. L. DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists. Neuropharmacology 38, 1577–1583 (1999).
Oliet, S. H., Malenka, R. C. & Nicoll R. A. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neuron 18, 969–982 (1997).
Kato, N. Dependence of long-term depression on metabotropic glutamate receptors in visual cortex. Proc. Natl. Acad. Sci. USA 90, 3650–3654 (1993).
Zheng, F. & Gallagher, J. P. Metabotropic glutamate receptors are required for the induction of long-term potentiation. Neuron 9, 163–172 (1992).
Bashir Z. I. et al. Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors. Nature 363, 347–350 (1993).
Aiba, A. et al. Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell 79, 365–375 (1994).
O'Connor, J. J., Rowan, M. J. & Anwyl, R. Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: investigations of the involvement of mGlu receptors. J. Neurosci. 15, 2013–2020 (1995).
Lebrand, C. et al. Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17, 823–835 (1996).
Bear, M. F. & Singer, W. Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 320, 172–176 (1986).
Sharma, J., Angelucci, A. & Sur, M. Induction of visual orientation modules in auditory cortex. Nature 404, 841–847 (2000).
Iwasato, T. et al. Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406, 726–731 (2000).
Dixon, J. F., Los, G. V. & Hokin, L. E. Lithium stimulates glutamate “release” and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-d-aspartate receptor in monkey and mouse cerebral cortex slices. Proc. Natl. Acad. Sci. USA 91, 8358–8362 (1994).
Husi, H., Ward, M. A., Choudhary, J. S., Blackstock, W. P. & Grant, S. G. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat. Neurosci. 3, 661–669 (2000).
Walikonis, R. S. et al. Identification of proteins in the postsynaptic density fraction by mass spectrometry. J. Neurosci. 20, 4069–4080 (2000).
Glazewski, S., Giese, K. P., Silva, A. & Fox, K. The role of α-CamKII autophosphorylation in neocortical experience-dependent plasticity. Nat. Neurosci. 3, 911–918 (2000).
Vitalis T. et al. Effects of monoamine oxidase A inhibition on barrel formation in the mouse somatosensory cortex: determination of a sensitive developmental period. J. Comp. Neurol. 393, 169–184 (1998).
Welker, E. & Van der Loos, H. Quantitative correlation between barrel-field size and the sensory innervation of the whiskerpad: a comparative study of six strains of mice bred for different patterns of mystacial vibrissae. J. Neurosci. 6, 3355–3373 (1986).
Schlagger, B. L., Fox, K. & O'Leary, D. D. M. Postsynaptic control of plasticity in developing somatosensory cortex. Nature 364, 623–626 (1993).
Fox, K., Schlagger, B. L., Glazewski, S. & O'Leary, D. D. M. Glutamate receptor blockade at cortical synapses disrupts development of thalamocortical and columnar organization in somatosensory cortex. Proc. Natl. Acad. Sci. USA 93, 5584–5589 (1996).
Chiaia, N. L., Fish, S. E., Bauer, W. R., Bennett-Clarke, C. A. & Rhoades, R. W. Postnatal blockade of cortical activity by tetrodotoxin does not disrupt the formation of vibrissa-related patterns in the rat's somatosensory cortex. Brain Res. Dev. Brain Res. 66, 244–250 (1992).
Henderson, T. A., Woolsey, T. A. & Jacquin, M. F. Infraorbital nerve blockade from birth does not disrupt central trigeminal pattern formation in the rat. Brain Res. Dev. Brain Res. 66, 146–152 (1992).
Westermann, P., Knoblich, M., Maier, O., Lindschau, C. & Haller H. Protein Kinase C supports the formation of constitutive transport vesicles. Biochem. J. 320, 651–658 (1996).
Sabatini, D. D., Adesnik, M., Ivanov, I. E. & Simon, J. P. Mechanism of formation of post Golgi vesicles from TGN membranes: Arf-dependent coat assembly and PKC-regulated vesicle scission. Biocell 20, 287–300 (1996).
Cases, O. et al. Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine A knock-outs. J. Neurosci. 18, 6914–6927 (1998).
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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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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