282 nature neuroscience • volume 4 no 3 • march 2001 articles The adult neocortex consists of a patchwork of fields serving dif- ferent functions. Major sensory and motor areas can be distin- guished by their cytoarchitecture, that is, their particular arrangement of neurons and neuropil. One issue in developmen- tal neurobiology concerns how cortical areas differentiate during development, and the involvement of neural activity in this process 1 . The primary somatosensory cortex of rodents is an ideal system for studying this problem, because it has particularly dis- tinct cytoarchitectonic features in layer 4, called ‘barrels,’ which represent individual facial vibrissae. Each mature barrel consists of a barrel-shaped ‘wall’ of densely-packed neurons, which extend their dendrites into a cell-sparse region in the center of the bar- rel, known as the barrel ‘hollow’ 2,3 . In each hollow is a dense bun- dle of axons from the ventroposterior (VP) complex of the thalamus, which synapse on the dendrites of the layer 4 neurons. As thalamic axons grow up through the lower layers of the cortex over the first two days after birth in mice, they organize themselves into bundles to form a barrel-like pattern 2,4–6 . Sub- sequently, this segregated array of axons reaches layer 4. The majority of neurons become displaced to form the barrel walls, and reorient their dendrites into the barrel hollows, where they receive synaptic contacts from their particular segregated bun- dle of thalamic afferents. The few remaining cortical neurons in the barrel hollow maintain symmetrically distributed den- drites 3,7,8 . Several lines of evidence suggest that the morphological reor- ganization and differentiation of cortical neurons to form bar- rels depend, at least in part, on signals conveyed by invading thalamic axons. For example, explants of the primordial visual cortex transplanted from the occipital lobe into the neonatal somatosensory cortex form barrels when invaded by axons from VP 9 . Moreover, a number of genetic manipulations that inter- fere with the appropriate segregation of VP axons totally disrupt barrel differentiation 10–12 . In mice with null mutations in either the monoamine oxidase A (MAOA) gene, which have elevated levels of serotonin, or the adenylyl cyclase 1 gene, ingrowing thal- amic axons fail to segregate to form the primordial barrel pat- tern, and cortical cells do not rearrange. However, these studies do not address the mechanism by which layer 4 neurons nor- mally rearrange themselves in response to the pre-formed pat- tern of thalamic axons. How do thalamic axons communicate with cortical neurons to stimulate their morphological differentiation? Although var- ious neurotransmitters and their receptors have been implicat- ed in activity-dependent cortical differentiation and plasticity 1 , little is known of the intracellular signaling pathways that medi- ate these processes. There is suggestive evidence, however, that phospholipase C-β1 (PLC-β1) is critically involved 13–15 . PLC-β1 is a postsynaptic, receptor-activated, G protein-coupled phos- phodiesterase, which hydrolyzes the phosphoinositide (PI) phos- phatidylinositol 4,5-biphosphate (PIP2) into the second messengers diacylglycerol (DAG) and 1,4,5-inositol triphosphate (IP3). In turn, DAG activates the phosphorylating enzyme pro- tein kinase C (PKC). IP3 regulates the release of Ca 2+ from the endoplasmic reticulum, and IP3, PIP2 and DAG all have direct effects on vesicular trafficking within the cell 16,17 . PLC-β1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex Anthony J. Hannan 1 , Colin Blakemore 1 , Alla Katsnelson 1 , Tania Vitalis 2 , Kimberly M. Huber 3 , Mark Bear 3 , John Roder 4 , Daesoo Kim 5 , Hee-Sup Shin 5 and Peter C. Kind 1,2 1 University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK 2 Department of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, Georges Square, Edinburgh, EH8 9XD, UK 3 Department of Neuroscience, Brown University, Providence, Rhode Island 02912, USA 4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto, Ontario, M5G 1X5, Canada 5 National CRI Center for Calcium and Learning, Department of Life Science, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea Correspondence should be addressed to P.K. (p.kind@ed.ac.uk) During development of the cerebral cortex, the invasion of thalamic axons and subsequent differen- tiation 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. © 2001 Nature Publishing Group http://neurosci.nature.com © 2001 Nature Publishing Group http://neurosci.nature.com