Tumor Necrosis Factor and Interleukin-1β Modulate Synaptic Plasticity during Neuroinflammation

Figure 1

LTP regulation in physiological and pathological states. The triggering of LTP implies coincident pre- and postsynaptic neuron activation. Strong glutamate release from presynaptic terminal promotes membrane depolarization mediated by Na⁺ influx through AMPARs (1), which in turn activates NMDARs by means of Mg²⁺ expulsion from NMDAR pore, thus allowing Ca²⁺ influx (2). Next, the increase of intracellular Ca²⁺ concentration activates a cascade of events involving several molecular players and leads to the induction of IEGs (3), such as Arc/Arg, necessary for structural (increased stability and size of dendritic spines) and functional changes of the PSD and the synthesis and insertion of AMPARs in membrane (4). Physiological levels of IL-1β released by both microglia and astroglia contribute to LTP phenomenon (a). During neuroinflammatory disorders (b), activated resident (microglia and astroglia) and infiltrating T-cells strongly release TNF and IL-1β, thus generating two possible outcomes of synaptic changes (A, B). As illustrated in the figure, LTP can be either potentiated or prevented through the action of TNF and IL-1β interfering with the pathways controlling the molecular and structural synaptic changes occurring during LTP.

(a)

(b)