Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca 2+ signaling

Sci Signal. 2018 Nov 27;11(558):eaat9093. doi: 10.1126/scisignal.aat9093.

Abstract

Acidic organelles, such as endosomes and lysosomes, store Ca2+ that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca2+ signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca2+ store signaling in murine hippocampal neurons. We found that metabotropic glutamate receptor 1 (mGluR1) was coupled to NAADP signaling that elicited Ca2+ release from acidic stores. In turn, this released Ca2+-mediated mGluR1-dependent LTP by transiently inhibiting SK-type K+ channels, possibly through the activation of protein phosphatase 2A. Genetically removing two-pore channels (TPCs), which are endolysosomal-specific ion channels, switched the polarity of plasticity from LTP to LTD, indicating the importance of specific receptor store coupling and providing mechanistic insight into how mGluR1 can produce both synaptic potentiation and synaptic depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels / physiology*
  • Calcium Signaling*
  • Cells, Cultured
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Long-Term Potentiation*
  • Male
  • Mice
  • Mice, Knockout
  • NADP / analogs & derivatives*
  • NADP / pharmacology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / physiology
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / metabolism*

Substances

  • Calcium Channels
  • Receptors, Metabotropic Glutamate
  • TPCN1 protein, mouse
  • TPCN2 protein, mouse
  • metabotropic glutamate receptor type 1
  • NADP
  • NAADP
  • Calcium