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The Journal of Neuroscience, March 15, 2003, 23(6):2323

Absence of Whisker-Related Pattern Formation in Mice with NMDA Receptors Lacking Coincidence Detection Properties and Calcium Signaling

York Rudhard^{1, 2, *}, Matthias Kneussel^{1, 2, *}, Mohammed A. Nassar^{1, 2}, Georg F. Rast^{1, 2}, Alexander J. Annala^{1, 2}, Philip E. Chen^{1, 2}, Cezar M. Tigaret^{1, 2}, Isabel Dean^{1, 4}, Juergen Roes⁵, Alasdair J. Gibb², Stephen P. Hunt³, and Ralf Schoepfer^{1, 2}

¹ Wellcome Laboratory for Molecular Pharmacology, ² Department of Pharmacology, ³ Department of Anatomy, ⁴ Wellcome Trust Neuroscience PhD program, and ⁵ Department of Medicine, University College London, London WC1E 6BT, United Kingdom

Precise refinement of synaptic connectivity is the result of activity-dependent mechanisms in which coincidence-dependent calcium signaling by NMDA receptors (NMDARs) under control of the voltage-dependent Mg²⁺ block might play a special role.

In the developing rodent trigeminal system, the pattern of synaptic connections between whisker-specific inputs and their target cells in the brainstem is refined to form functionally and morphologically distinct units (barrelettes). To test the role of NMDA receptor signaling in this process, we introduced the N598R mutation into the native NR1 gene. This leads to the expression of functional NMDARs that are Mg²⁺ insensitive and Ca²⁺ impermeable.

Newborn mice expressing exclusively NR1 N598R-containing NMDARs do not show any whisker-related patterning in the brainstem, whereas the topographic projection of trigeminal afferents and gross brain morphology appear normal. Furthermore, the NR1 N598R mutation does not affect expression levels of NMDAR subunits and other important neurotransmitter receptors.

Our results show that coincidence detection by, and/or Ca²⁺ permeability of, NMDARs is necessary for the development of somatotopic maps in the brainstem and suggest that highly specific signaling underlies synaptic refinement.

Key words: barrelette; somatosensory; whisker; trigeminal pathway; pattern formation; topographic map; NMDA receptor; NMDAR; coincidence detection; point mutation; knock-in; homologous recombination; cytochrome oxidase; DiI labeling; Mg²⁺ block; Ca²⁺-dependent signaling; brainstem; Cre recombinase; loxP; Tenascin; boundary

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^* Y.R. and M.K. contributed equally to this work.

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2362323-10$05.00/0

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