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

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 as well as 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 endo-lysosomal-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. 2

Contribution of NAADP to Glutamate-Evoked Changes in Ca2+ Homeostasis in Mouse Hippocampal Neurons

“…In addition to ionotropic NMDA, AMPA, and KA receptors, glutamate activates mGluRs to elicit downstream signaling events in the cell ( Reiner and Levitz, 2018 ). It was shown that stimulation of hippocampal neurons with glutamate triggers NAADP synthesis probably via activation of mGluR1 receptors and mediates calcium release from lysosomal stores via two-pore-channels ( Bak et al, 1999 ; McGuinness et al, 2007 ; Pandey et al, 2009 ; Foster et al, 2018 ). The prerequisite for this process is the loading of acidic stores with calcium ions which depends on the activity of the V-ATPase ( Figure 1 ) and acidification that then allows Ca 2+ uptake via H + /Ca 2+ exchange.…”

“…In the CNS and particularly in hippocampal neurons glutamate induces the synthesis of nicotinic acid adenine dinucleotide phosphate (NAADP) and subsequent Ca 2+ release ( Bak et al, 1999 ; McGuinness et al, 2007 ; Pandey et al, 2009 ). NAADP can be produced following activation of mGuR1 receptors and is known to mediate Ca 2+ release into the cytosol via activation of two-pore channels 1/2 (TPC1/2) residing in the membrane of endo-lysosomal Ca 2+ stores in many cell types including neurons ( Bayraktar et al, 1990 ; Patel, 2015 ; Grimm et al, 2017 ; Foster et al, 2018 ) resulting in Ca 2+ flux into the cytoplasm. Recently, it was also shown that Ca 2+ entry via voltage gated Ca 2+ channels triggers Ca 2+ release from the lysosome via an NAADP-sensitive channel and, subsequently, fusion of the lysosome with the plasma membrane ( Padamsey et al, 2017 ).…”

“…A recent study has also shown that Ca 2+ entry via voltage gated Ca 2+ channels triggers Ca 2+ release from the lysosome via an NAADP-sensitive channel and, subsequently, fusion of the lysosome with the plasma membrane (Padamsey et al, 2017). In addition, metabotropic glutamate receptor 1 (mGluR1) has been reported to couple to NAADP signaling eliciting Ca 2+ release from acidic stores via TPC channels during synaptic plasticity (Foster et al, 2018). In non-neuronal cells the NAADP-evoked Ca 2+ release depends on ryanodine receptors, such as on Ryanodine Receptors type 1 (RYR1) in T cells (Diercks et al, 2018), and on TRPML1 channels in fibroblasts (Zhang et al, 2011).…”

Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors

“…Together these reports suggest similar preclinical efficacies by mGlu 1 PAMs and NAMs, but more research is necessary to discern possible desperate mechanisms of action. While these studies mentioned focus primarily on the positive symptoms related to schizophrenia, mGlu 1 receptors are positioned in critical brain areas such as the hippocampus [35] and prefrontal cortex [36] to suggest that they can be modulated to enhance cognitive function and possibly treat cognitive and negative domains of this disorder as well. These other domains are likely to be thoroughly investigated as mGlu 1 is still in a preclinical stage of validation as a target for schizophrenia.…”

Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

“…Like IP 3 , both nucleotide messengers are known to regulate a wide range of physiological functions and in a variety of cell types spanning three biological kingdoms (reviewed in Refs. [11][12][13][14][15][16], including mediating the adrenergic receptor activation in the salivary gland (17) and the hippocampal mGluR1-dependent long-term potentiation (18), shown recently.…”