Transregional astrocyte-dependent metaplasticity in the hippocampus

Learning-related synaptic plasticity is regulated by metaplasticity, which adjusts plasticity thresholds in an activity-dependent manner. We have previously described a heterodendritic form of metaplasticity whereby priming stimulation in stratum oriens (SO) inhibits subsequent long-term potentiation (LTP) in the neighboring stratum radiatum of the hippocampal CA1 region. Here, we report that this metaplasticity is, in fact, transregional, in that the SO priming stimulation also inhibits later LTP induction at dentate gyrus (DG) middle molecular layer (MML) synapses, both in vitro and in vivo. This effect operates across the hippocampal fissure since it occurs in the absence of CA3, thus highlighting a previously unappreciated reverse-direction and long-distance hippocampal crosstalk. Our findings demonstrate an essential role of astrocytes as SO priming elicited a sustained increase in the frequency of calcium (Ca2+) events in astrocytes in the DG MML, while the metaplasticity effect was blocked by calcium-buffering in MML astrocytes. It could be triggered by either activation of M1 muscarinic acetylcholine receptors or group II metabotropic glutamate receptors, and was critically dependent on inositol 1,4,5-trisphosphate receptor type 2 signaling. The transregional inhibition of LTP was mediated by astrocytic release of tumor necrosis factor (TNF), which likely acts in an autocrine fashion on astrocytic TNF type 1 receptors (TNFR1s). Downstream of TNF-TNFR1 signaling, the inhibition of MML LTP was mediated by the activation of GluN2B-containing N-methyl-D-aspartate receptors. Thus, a complex, bidirectional neuron-glia signaling cascade orchestrates long-distance metaplasticity across hippocampal subregions, providing a novel framework for understanding how hippocampal neuronal networks dynamically regulate plasticity thresholds across space and time. Significance StatementThis study documents the existence of a transregional metaplasticity that traverses from area CA1 to the dentate gyrus across the hippocampal fissure. This reveals a novel long-distance crosstalk within the hippocampus, in addition to the classical pathways of information transfer. This form of metaplasticity entails an essential contribution by astrocytes that integrate neuronal activity and use a complex Ca2+-dependent neuron-glia-neuron signaling cascade to dynamically regulate LTP thresholds in the hippocampal dentate gyrus.