Figure 2

Ca²⁺ Signaling and synaptic maintenance. A. Synaptic maintenance requires continuous trans-synaptic signaling at excitatory synapse. Spontaneous release of glutamate triggers activation of NMDA receptors (NMDAR) and Ca²⁺ elevation in the postsynaptic terminal. Low levels of Ca²⁺ in postsynaptic ER causes Ca²⁺ influx via the nSOC pathway. These Ca²⁺ signals continuously stimulate activity of CaMKII, which is necessary for maintenance of synaptic spine structure. B. Similar Ca²⁺ signaling defects are observed at the presynaptic terminal and postsynaptic spines in synapses that old, exhibit premature loss of maintenance machinery or in Alzheimer’s Disease (AD). The frequency of spontaneous glutamate release is diminished in both aging and AD neurons. Ca²⁺ influx via NMDARs is reduced. Mitochondria are depolarized and less effective in Ca²⁺ uptake. The levels of cytosolic CaBPs are reduced. The ER Ca²⁺ levels are increased and synaptic nSOC is diminished. As a result of these changes the activity of CaMKII at the synapse is reduced and activity of CaN is elevated, leading to weakening and destabilization of the synapses in aging and AD neurons by promoting “LTD-like” signaling pathways. Similar, but more severe, processes are observed in PS-FAD neurons. Red arrows indicate increased or decreased activity. ER - endoplasmic reticulum; AV - autophagic vacuole; Mito - Mitochondrium; EE - early endosome; EV - endocytic vesicle; SV - synaptic vesicle; nSOC - neuronal store-operated Ca²⁺ entry; NMDAR - NMDA receptor; CamK2 - Ca/CaM Kinase 2; CaN - Calcineurin; CaBP - Calcium binding protein; PSEN - Presenilin.