State-dependent cAMP sensitivity of presynaptic function underlies metaplasticity in a hippocampal feedforward inhibitory circuit

Neuron. 2008 Dec 26;60(6):980-7. doi: 10.1016/j.neuron.2008.11.018.

Abstract

At hippocampal mossy fiber (MF)-st. lucidum interneuron (SLIN) synapses, mGluR7 serves as a metaplastic switch controlling bidirectional plasticity. mGluR7 activation during high-frequency stimulation (HFS) triggers presynaptic LTD due to persistent P/Q-type Ca(2+) channel inhibition. However, following mGluR7 internalization HFS produces presynaptic LTP. Surprisingly, LTP is not a simple molecular reversal of Ca(2+) channel depression. Rather, mGluR7 activation/internalization controls plasticity polarity by gating cAMP sensitivity of release. While naive surface mGluR7 expressing MF-SLIN synapses are insensitive to cAMP elevation, synapses that have internalized mGluR7 robustly potentiate following cAMP increases. Moreover, MF-SLIN LTP requires adenylate cyclase (AC) and protein kinase A (PKA) activities. We also discovered an association between mGluR7 and RIM1alpha, an active zone molecule required for AC/PKA-dependent presynaptic LTP. Importantly, the mGluR7-RIM1alpha interaction is regulated by mGluR7 activation, and mice lacking RIM1alpha are deficient in MF-SLIN LTP. We conclude that state-dependent cAMP sensitivity controlled by mGluR7-RIM1alpha interactions underlies MF-SLIN metaplasticity.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Anthracenes / pharmacology
  • Biophysics
  • Calcium / metabolism
  • Cyclic AMP / metabolism*
  • Dose-Response Relationship, Drug
  • Electric Stimulation / methods
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Proteins / deficiency
  • Hippocampus / cytology*
  • Immunoprecipitation / methods
  • Isoquinolines / pharmacology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / physiology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Presynaptic Terminals / drug effects*
  • Propionates / pharmacology
  • Receptors, Metabotropic Glutamate / metabolism
  • Sulfonamides / pharmacology
  • Synapses / drug effects*
  • Synapses / physiology

Substances

  • 2,3-didecyloxyanthracene
  • 2-amino-4-phosphono-propinate
  • Anthracenes
  • Enzyme Inhibitors
  • Isoquinolines
  • Propionates
  • Receptors, Metabotropic Glutamate
  • Rims1 protein, mouse
  • Sulfonamides
  • metabotropic glutamate receptor 7
  • Cyclic AMP
  • GTP-Binding Proteins
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Calcium