Neurexins Induce Differentiation of GABA and Glutamate Postsynaptic Specializations via Neuroligins

Formation of synaptic connections requires alignment of neurotransmitter receptors on postsynaptic dendrites opposite matching transmitter release sites on presynaptic axons. beta-neurexins and neuroligins form a trans-synaptic link at glutamate synapses. We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. Surprisingly, neurexin also induces GABA postsynaptic differentiation. Conversely, neuroligins induce presynaptic differentiation in both glutamate and GABA axons. Whereas neuroligins-1, -3, and -4 localize to glutamate postsynaptic sites, neuroligin-2 localizes primarily to GABA synapses. Direct aggregation of neuroligins reveals a linkage of neuroligin-2 to GABA and glutamate postsynaptic proteins, but the other neuroligins only to glutamate postsynaptic proteins. Furthermore, mislocalized expression of neuroligin-2 disperses postsynaptic proteins and disrupts synaptic transmission. Our findings indicate that the neurexin-neuroligin link is a core component mediating both GABAergic and glutamatergic synaptogenesis, and differences in isoform localization and binding affinities may contribute to appropriate differentiation and specificity.

[1]  T. Südhof,et al.  Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin. , 1992, Science.

[2]  N. Ziv,et al.  Molecular mechanisms of CNS synaptogenesis , 2002, Trends in Neurosciences.

[3]  A. Craig,et al.  Molecular heterogeneity of central synapses: afferent and target regulation , 2001, Nature Neuroscience.

[4]  R. Fetter,et al.  Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons , 2000, Cell.

[5]  Michael E Greenberg,et al.  EphB Receptors Interact with NMDA Receptors and Regulate Excitatory Synapse Formation , 2000, Cell.

[6]  T. Südhof,et al.  α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis , 2003, Nature.

[7]  Noam E Ziv,et al.  Assembly of New Individual Excitatory Synapses Time Course and Temporal Order of Synaptic Molecule Recruitment , 2000, Neuron.

[8]  T. Südhof,et al.  Neurexophilin binding to alpha-neurexins. A single LNS domain functions as an independently folding ligand-binding unit. , 1998, The Journal of biological chemistry.

[9]  T. Südhof,et al.  A stoichiometric complex of neurexins and dystroglycan in brain , 2001, The Journal of cell biology.

[10]  T. Südhof,et al.  Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing. , 2002, Genomics.

[11]  J. Sanes,et al.  Synaptic adhesion molecules. , 2003, Current opinion in cell biology.

[12]  G. Feng,et al.  Synapse formation by hippocampal neurons from agrin-deficient mice. , 1999, Developmental biology.

[13]  T. Südhof,et al.  Interaction of synaptotagmin with the cytoplasmic domains of neurexins , 1993, Neuron.

[14]  G. Banker,et al.  Culturing nerve cells , 1998 .

[15]  K. Frei,et al.  Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression. , 2001, The Biochemical journal.

[16]  T. Südhof,et al.  Structures, Alternative Splicing, and Neurexin Binding of Multiple Neuroligins (*) , 1996, The Journal of Biological Chemistry.

[17]  T. Südhof,et al.  Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  L. Brodin Faculty Opinions recommendation of Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. , 2003 .

[19]  J. Duncan,et al.  An adaptive coding model of neural function in prefrontal cortex , 2001, Nature Reviews Neuroscience.

[20]  M. Sheng,et al.  Postsynaptic Signaling and Plasticity Mechanisms , 2002, Science.

[21]  E. Isacoff,et al.  Neurexin mediates the assembly of presynaptic terminals , 2003, Nature Neuroscience.

[22]  T. Südhof,et al.  Mints as Adaptors , 2000, The Journal of Biological Chemistry.

[23]  O. Steward,et al.  Synaptic Clustering of AMPA Receptors by the Extracellular Immediate-Early Gene Product Narp , 1999, Neuron.

[24]  M. Kennedy,et al.  Signal-processing machines at the postsynaptic density. , 2000, Science.

[25]  J. Deisenhofer,et al.  Regulation of LNS Domain Function by Alternative Splicing: The Structure of the Ligand-Binding Domain of Neurexin Iβ , 1999, Cell.

[26]  T. Südhof,et al.  SynCAM, a Synaptic Adhesion Molecule That Drives Synapse Assembly , 2002, Science.

[27]  J. Sanes,et al.  Dystroglycan Is Selectively Associated with Inhibitory GABAergic Synapses But Is Dispensable for Their Differentiation , 2002, The Journal of Neuroscience.

[28]  Yu Tian Wang,et al.  A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  T. Südhof,et al.  Structure and Evolution of Neurexophilin , 1996, The Journal of Neuroscience.

[30]  K. Campbell,et al.  Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy , 2002, Nature.

[31]  C. Keller,et al.  Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. , 2004, Pharmacology & therapeutics.

[32]  Michelle N. Ngo,et al.  Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus , 2003, The Journal of cell biology.

[33]  M. Ruegg,et al.  Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site , 1995, The Journal of cell biology.

[34]  T. Südhof,et al.  Neuroligin 1: A splice site-specific ligand for β-neurexins , 1995, Cell.

[35]  Albert David,et al.  X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. , 2004, American journal of human genetics.

[36]  T. Südhof,et al.  Cartography of neurexins: More than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons , 1995, Neuron.

[37]  S. Lévi,et al.  Gephyrin Is Critical for Glycine Receptor Clustering But Not for the Formation of Functional GABAergic Synapses in Hippocampal Neurons , 2004, The Journal of Neuroscience.

[38]  Thomas Bourgeron,et al.  Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism , 2003, Nature Genetics.

[39]  J. Sanes,et al.  Induction, assembly, maturation and maintenance of a postsynaptic apparatus , 2001, Nature reviews. Neuroscience.

[40]  I. Knuesel,et al.  Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice) , 1999, The European journal of neuroscience.

[41]  T. Südhof,et al.  Binding of neuroligins to PSD-95. , 1997, Science.

[42]  H. Wässle,et al.  Reduced synaptic clustering of GABA and glycine receptors in the retina of the gephyrin null mutant mouse , 2000, The Journal of comparative neurology.

[43]  A. Craig,et al.  Mismatched Appositions of Presynaptic and Postsynaptic Components in Isolated Hippocampal Neurons , 2000, The Journal of Neuroscience.

[44]  M. Sheng,et al.  Heterogeneity in the Molecular Composition of Excitatory Postsynaptic Sites during Development of Hippocampal Neurons in Culture , 1998, The Journal of Neuroscience.