title: Disruption of Coordinated Presynaptic and Postsynaptic Maturation Underlies the Defects in Hippocampal Synapse Stability and Plasticity in Abl2/Arg-Deficient Mice.
abstract: Immature glutamatergic synapses in cultured neurons contain high-release probability (Pr) presynaptic sites coupled to postsynaptic sites bearing GluN2B-containing NMDA receptors (NMDARs), which mature into low-Pr, GluN2B-deficient synapses. Whether this coordinated maturation of high-Pr, GluN2B(+) synapses to low-Pr, GluN2B-deficient synapses actually occurs in vivo, and if so, what factors regulate it and what role it might play in long-term synapse function and plasticity are unknown. We report that loss of the integrin-regulated Abl2/Arg kinase in vivo yields a subpopulation of "immature" high-Pr, GluN2B(+) hippocampal synapses that are maintained throughout late postnatal development and early adulthood. These high-Pr, GluN2B(+) synapses are evident in arg(-/-) animals as early as postnatal day 21 (P21), a time that precedes any observable defects in synapse or dendritic spine number or structure in arg(-/-) mice. Using focal glutamate uncaging at individual synapses, we find only a subpopulation of arg(-/-) spines exhibits increased GluN2B-mediated responses at P21. As arg(-/-) mice age, these synapses increase in proportion, and their associated spines enlarge. These changes coincide with an overall loss of spines and synapses in the Arg-deficient mice. We also demonstrate that, although LTP and LTD are normal in P21 arg(-/-) slices, both forms of plasticity are significantly altered by P42. These data demonstrate that the integrin-regulated Arg kinase coordinates the maturation of presynaptic and postsynaptic compartments in a subset of hippocampal synapses in vivo, and this coordination is critical for NMDAR-dependent long-term synaptic stability and plasticity.
  
  
  
  Synapses mature in vitro from high-release probability (Pr) GluN2B(+) to low-Pr, GluN2B(-), but it is unknown why this happens or whether it occurs in vivo High-Pr, GluN2B(+) synapses persist into early adulthood in Arg-deficient mice in vivo and have elevated NMDA receptor currents and increased structural plasticity. The persistence of these high-Pr, GluN2B(+) synapses is associated with a net synapse loss and significant disruption of normal synaptic plasticity by early adulthood. Together, these observations suggest that the maturation of high-Pr, GluN2B(+) synapses to predominantly low-Pr, GluN2B(-) synapses may be essential to preserving a larger dynamic range for plasticity while ensuring that connectivity is distributed among a greater number of synapses for optimal circuit function.
authors.affiliation: Department of Molecular Biophysics and Biochemistry.
authors.forename: Xiao
authors.identifier: 0000-0002-4328-0634
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Interdepartmental Neuroscience Program.
authors.forename: Aaron D
authors.identifier: 0000-0002-5856-8294
authors.initials: AD
authors.lastname: Levy
authors.affiliation: Departments of Cell Biology and.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Rosenberg
authors.affiliation: Neuroscience, and Program in Cellular Neuroscience, Degeneration and Repair, Yale University, New Haven, Connecticut 06520-8024.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Higley
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Interdepartmental Neuroscience Program, Neuroscience, and Program in Cellular Neuroscience, Degeneration and Repair, Yale University, New Haven, Connecticut 06520-8024 anthony.koleske@yale.edu.
authors.forename: Anthony J
authors.identifier: 0000-0003-4105-9909
authors.initials: AJ
authors.lastname: Koleske
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D049229:Dendritic Spines / Q000235:genetics / Q000502:physiology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018698:Glutamic Acid / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics
chemical_list: D018683:Excitatory Amino Acid Agents; D018840:HSP70 Heat-Shock Proteins; C121001:NR2B NMDA receptor; D018377:Neurotransmitter Agents; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases
keywords: NMDA receptor; hippocampus; integrin–Arg signaling; maturation; synaptic plasticity; synaptic stability