title: Absence of Whisker-related pattern formation in mice with NMDA receptors lacking coincidence detection properties and calcium signaling.
abstract: 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.
authors.affiliation: Wellcome Laboratory for Molecular Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: York
authors.initials: Y
authors.lastname: Rudhard
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nassar
authors.forename: Georg F
authors.initials: GF
authors.lastname: Rast
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Annala
authors.forename: Philip E
authors.initials: PE
authors.lastname: Chen
authors.forename: Cezar M
authors.initials: CM
authors.lastname: Tigaret
authors.forename: Isabel
authors.initials: I
authors.lastname: Dean
authors.forename: Juergen
authors.initials: J
authors.lastname: Roes
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Gibb
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunt
authors.forename: Ralf
authors.initials: R
authors.lastname: Schoepfer
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D018390:Gene Targeting; D005799:Genes, Dominant; D005804:Genes, Lethal; D005838:Genotype; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism*; D012119:Respiration / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism; D014276:Trigeminal Nerve / Q000166:cytology / Q000378:metabolism; D014738:Vibrissae / Q000294:innervation / Q000502:physiology*
chemical_list: C409466:NR1 NMDA receptor; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D008274:Magnesium; D002118:Calcium