Abstract
The induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission entails pre- and postsynaptic Ca2+ signals, which represent transient increments in cytoplasmic free Ca2+ concentration. In diverse synapse types, Ca2+ release from intracellular stores contributes to amplify the Ca2+ signals initially generated by activation of neuronal Ca2+ entry pathways. Here, we used hippocampal slices from young male rats to evaluate whether pharmacological activation or inhibition of Ca2+ release from the endoplasmic reticulum (ER) mediated by ryanodine receptor (RyR) channels modifies LTD induction at Schaffer collateral-CA1 synapses. Pre-incubation of slices with ryanodine (1 μM, 1 h) or caffeine (1 mM, 30 min) to promote RyR-mediated Ca2+ release facilitated LTD induction by low frequency stimulation (LFS), but did not affect the amplitude of synaptic transmission, the profiles of field excitatory postsynaptic potentials (fEPSP) or the paired-pulse (PP) responses. Conversely, treatment with inhibitory ryanodine (20 μM, 1 h) to suppress RyR-mediated Ca2+ release prevented LTD induction, but did not affect baseline synaptic transmission or PP responses. Previous literature reports indicate that LTD induction requires presynaptic CaMKII activity. We found that 1 h after applying the LTD induction protocol, slices displayed a significant increase in CaMKII phosphorylation relative to the levels exhibited by un-stimulated (naïve) slices. In addition, LTD induction (1 h) enhanced the phosphorylation of the presynaptic protein Synapsin I at a CaMKII-dependent phosphorylation site, indicating that LTD induction stimulates presynaptic CaMKII activity. Pre-incubation of slices with 20 μM ryanodine abolished the increased CaMKII and Synapsin I phosphorylation induced by LTD, whereas naïve slices pre-incubated with inhibitory ryanodine displayed similar CaMKII and Synapsin I phosphorylation levels as naïve control slices. We posit that inhibitory ryanodine suppressed LTD-induced presynaptic CaMKII activity, as evidenced by the suppression of Synapsin I phosphorylation induced by LTD. Accordingly, we propose that presynaptic RyR-mediated Ca2+ signals contribute to LTD induction at Schaffer collateral-CA1 synapses.
Highlights
Evidence gathered in the last three decades supports long-term potentiation (LTP) and long-term depression (LTD) as likely cellular correlates of associative learning and long-term memory (Dudek and Bear, 1992; Bliss and Collingridge, 1993; Bear and Abraham, 1996; Malenka and Bear, 2004; Whitlock et al, 2006; Raymond, 2007; Citri and Malenka, 2008; Lynch et al, 2014; Nabavi et al, 2014)
We found that 1 μM or 20 μM ryanodine, or 1 mM caffeine did not modify fiber volley (FV) amplitude, suggesting that these drugs do not affect presynaptic components involved in basal synaptic transmission
We found that 1 h after LTD induction slices exhibited a significant increase in CaMKII (α and β) and Synapsin I phosphorylation; these increments did not occur in slices treated with inhibitory ryanodine prior to exposure to the LTD induction protocol
Summary
Evidence gathered in the last three decades supports long-term potentiation (LTP) and long-term depression (LTD) as likely cellular correlates of associative learning and long-term memory (Dudek and Bear, 1992; Bliss and Collingridge, 1993; Bear and Abraham, 1996; Malenka and Bear, 2004; Whitlock et al, 2006; Raymond, 2007; Citri and Malenka, 2008; Lynch et al, 2014; Nabavi et al, 2014) Both LTP and LTD require increments in postsynaptic intracellular Ca2+ concentration (Mulkey and Malenka, 1992), which occur initially by means of Ca2+ influx through N-methyl-D-aspartate (NMDA) receptors or voltage-gated Ca2+ channels (Dudek and Bear, 1992; Mulkey and Malenka, 1992; Citri and Malenka, 2008). RyR channel activation facilitates learning and memory formation whereas inhibition of RyR activity or expression impairs these processes (Zhao et al, 2000; Edwards and Rickard, 2006; Galeotti et al, 2008; Adasme et al, 2011; Hidalgo and Arias-Cavieres, 2016; More et al, 2018)
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