Long-term potentiation (LTP) is a memory mechanism that is a highly regulated process, including by mechanisms of metaplasticity.  Recently, we discovered a unique transregional metaplasticity effect in the hippocampus whereby “priming” activity in stratum oriens of area CA1 selectively inhibits later LTP at synapses in stratum radiatum (SR) of CA1 but not in other CA1 lamina. Surprisingly, LTP at synapses in the middle molecular layer (MML) of the dentate gyrus is also inhibited. We hypothesized that this unusual transregional communication is accomplished by activation of the astrocyte network. We undertook intracellular astrocyte patch-clamping and extracellular field potential recordings in hippocampal slices taken from young adult rats and mice. In rat slices, Ca²⁺ was buffered in individually patched astrocytes by dialyzing EGTA while recording local synaptic potentials in SR (in the presence of D-serine) and MML (in the presence of glycine). Priming in control conditions inhibited LTP in both SR and MML while buffering astrocytic Ca²⁺ prevented the inhibition of LTP. Moreover, the priming effect was absent in IP3R2 knock-out mice. Finally, we found that the cytokine tumor necrosis factor-alpha (TNF), released by astrocytes and acting on TNF receptor-1, plus glutamate acting on GluN2BRs, are critical signaling molecules. Together, these data demonstrate a novel hippocampus-wide but synapse-selective regulation of LTP mediated by bidirectional astrocyte-neuron communication. We propose that such metaplasticity may play an important role in hippocampal information processing while also contributing to plasticity and memory impairments when aberrantly engaged under conditions of neuroinflammation.  

Jones and Sateesh, Joint first authors