Disruption of Coordinated Presynaptic and Postsynaptic Maturation Underlies the Defects in Hippocampal Synapse Stability and Plasticity in Abl2/Arg-Deficient Mice

J Neurosci. 2016 Jun 22;36(25):6778-91. doi: 10.1523/JNEUROSCI.4092-15.2016.

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.

Significance statement: 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.

Keywords: NMDA receptor; hippocampus; integrin–Arg signaling; maturation; synaptic plasticity; synaptic stability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Dendritic Spines / genetics
  • Dendritic Spines / physiology*
  • Excitatory Amino Acid Agents / pharmacology
  • Female
  • Gene Expression Regulation, Developmental / genetics*
  • Glutamic Acid / pharmacology
  • HSP70 Heat-Shock Proteins / metabolism
  • Hippocampus / cytology*
  • Hippocampus / growth & development
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • Neurotransmitter Agents / pharmacology
  • Protein-Tyrosine Kinases / deficiency*
  • Protein-Tyrosine Kinases / genetics
  • Receptors, Glutamate / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Synapses / drug effects
  • Synapses / physiology*
  • Synaptic Potentials / drug effects
  • Synaptic Potentials / genetics

Substances

  • Excitatory Amino Acid Agents
  • HSP70 Heat-Shock Proteins
  • NR2B NMDA receptor
  • Neurotransmitter Agents
  • Receptors, Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • ARG tyrosine kinase
  • Protein-Tyrosine Kinases