Fig. 8. Summary of an intracellular Mg²⁺-mediated pathway regulating synaptic configuration.

a Schematic to show that the synaptic configuration is a biomarker for dendritic branch-specific synaptic computations. Intracellular Mg²⁺ regulates the configuration and optimizes computational properties of nearby synapses along individual branches, including transmission efficiency, plasticity, and coding capacity (see Discussion). b A [Mg²⁺]_i-mediated regulatory pathway (left, schematic pathway; top-right, regulatory scheme in a bouton). In brief, [Mg²⁺]_i exerts a dual effect on D and Pr. On the one hand, [Mg²⁺]_i enhances mitochondrion (Mito) functions by increasing Mito number and membrane potential (ΔΨ)³⁸. This leads to an increase in intracellular free ATP levels ([ATP]_i), promoting the anterograde fast axonal transport (FAT) of CaSPs³⁸. As a result, presynaptic [CaSPs] increases, converting a remarkable portion of synapses from silent to functional and increasing D. On the other hand, it has an ongoing negative effect on Pr likely by competing with intracellular Ca²⁺ on presynaptic Ca²⁺-binding proteins (CBPs) (top-right). Overall, the changes in [Mg²⁺]_i lead to varying synaptic configurations across individual dendritic branches. Notably, at presynaptic sites, the strength of vesicle release during bursting transmission is dominantly determined by both burst-induced facilitation of presynaptic Ca²⁺ influx and [CaSPs], suggesting a regulatory scheme: ↑[Mg²⁺]_i → ↑ [CaSPs] → ↑ Pr_burst. In synergy, the increase in [ATP]_i accompanied by elevated [Mg²⁺]_i can well support the high-energy demand of vesicle turnover during bursting transmission. Consequently, ↑[Mg²⁺]_i causes increases in both ΣPr_burst and short-term facilitation (STF, =ΣPr_burst/ΣPr) at dendritic branches. At postsynaptic sites, elevated [Mg²⁺]_i induces an increase in [GluN2B], enhancing Ca²⁺ influx via GluN2B*NMDARs in dendritic spines ([Ca²⁺]^burst_spine) during bursting transmission. Hence, both pre- and postsynaptic sites synergize burst-induced synaptic plasticity^83,111. Overall, the synaptic configuration, crucially regulated by [Mg²⁺]_i, determines branch-specific synaptic computations during information processing.