IMPAIRED RYANODINE RECEPTOR–MEDIATED CA²⁺ RELEASE COMPROMISES EXCITATORY SYNAPTIC TRANSMISSION AT THE ONSET OF ALZHEIMER’S DISEASE

Dysregulation of Ca²⁺ homeostasis has been shown to be associated with the early onset of Alzheimer’s disease (AD). The Ca²⁺ release from intracellular stores is crucial for regulating cellular functions such as secretion, synaptic transmission and gene expression. Ryanodine receptors (RyRs) are Ca²⁺-permeable channels located on the endoplasmic reticulum membrane that play a key role in intracellular Ca²⁺ homeostasis by mediating Ca²⁺ release from intracellular stores. However, their precise contribution to Ca²⁺-dependent mechanisms underlying synaptic transmission remains to be elucidated. Here, we investigated the contribution of RyR-mediated Ca²⁺ release at excitatory synapses and whether they are impaired during AD-onset. We observed that while pharmacological inhibition of RyRs with dantrolene did not affect the average amplitude of evoked excitatory postsynaptic currents (eEPSCs), it significantly reduced the paired-pulse ratio (PPR) and attenuated eEPSC amplitudes during high-frequency stimulation. Conversely, in 3xtg-AD mice the PPR is potentiated and the eEPSCs amplitudes during high-frequency stimulation is more sustained as compared to the control conditions. Finally, the rate of vesicles recycling, reduced by dantrolene administration, is potentiated in AD-like models. Accordingly to previous observation indicating that AD onset is responsible for triggering calcium release from RyRs, we observed that dantrolene administration to Aβ-42-treated cells and 3xTg-AD hippocampal slices restored PPR to control conditions. Taken together, our findings indicate that RyRs play a key role in sustaining glutamate release and supporting vesicles recycling during periods of intense synaptic activity and suggest that their dysregulation may contribute to early synaptic dysfunction associated with AD onset.