Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca2+ signaling

Acidic Ca2+ stores in synaptic plasticityNeurotransmitter signaling and neuronal Ca2+ fluxes are critical to learning and memory. Foster et al. found connections between the glutamate receptor mGluR1 and so-called “acidic Ca2+ stores” (Ca2+ stored in acidic organelles) in mouse hippocampal neurons (see the Focus by Patel and Brailoiu). Activation of mGluR1 induced the production of the molecule NAADP, which triggered a cascade of organellar ion channel–mediated Ca2+ release from relatively acidic endosomes and lysosomes to the endoplasmic reticulum. The resulting increase in intracellular Ca2+ depolarized the neurons by paradoxically inhibiting Ca2+-activated SK-type K+ channels, possibly through Ca2+-dependent activation of a phosphatase. These findings identify potential therapeutic targets for patients with neuronal disorders associated with mGluR1 and lysosomal dysfunction.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.