Ryanodine receptors-mediated Calcium release and synaptic functions implications in Alzheimer's Disease onset

Ryanodine receptors (RyRs) are intracellular calcium channels expressed on the membrane of the endoplasmic reticulum (ER). They are primarily known for their pivotal role in calcium-induced calcium release (CICR), a process where the entry of calcium into the cell triggers the release of additional calcium from internal stores, amplifying the calcium signal and regulating different cellular functions. In neurons, calcium plays a pivotal role in the modulation of synaptic transmission, mediating neurotransmitter release and modulating synaptic plasticity by triggering vesicle fusion and influencing the dynamics of excitatory and inhibitory synapses. Although RyRs dysfunction has been linked to various neurodegenerative disorders, such as Alzheimer's disease, their precise involvement in the modulation of synaptic transmission remains poorly understood. This study investigates the role of RyR-mediated calcium release central synapses under physiological conditions, focusing on its contribution to neurotransmitter release, short-term synaptic plasticity and calcium-dependent inactivation (CDI) of voltage gated calcium channels localized at presynaptic membrane. Using pharmacological inhibition of RyRs with dantrolene, excitatory postsynaptic currents (eEPSCs) were analysed in autaptic hippocampal neurons. The research indicates that while RyR inhibition does not affect the amplitude of single eEPSCs, it significantly reduces paired pulse facilitation (PPF), suggesting the involvement of RyRs in the modulation of short-term synaptic plasticity during repetitive stimuli. Additionally, RyR inhibition alters CDI by reducing the inactivation of non-L-type calcium channels, suggesting that RyRs regulate presynaptic calcium dynamics through feedback mechanisms. These results highlight the critical but unexplored role of RyRs in maintaining synaptic efficacy during physiological neuronal activity, providing a foundation for further studies into their broader contributions to synaptic function and neurological health.