Transregional astrocyte-dependent metaplasticity in the hippocampus

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Astrocyte Biology

Background:

• Metaplasticity regulates synaptic plasticity by adjusting plasticity thresholds.
• Previous work identified heterodendritic metaplasticity in the hippocampal CA1 region.
• This study investigates metaplasticity's influence across different hippocampal subregions.

Purpose of the Study:

• To investigate if metaplasticity induced in stratum oriens (SO) affects long-term potentiation (LTP) in the dentate gyrus (DG).
• To elucidate the cellular and molecular mechanisms underlying this transregional metaplasticity.
• To explore the role of astrocytes and specific signaling pathways in mediating this effect.

Main Methods:

• In vitro and in vivo electrophysiological recordings in hippocampal slices and freely moving rats.
• Calcium imaging in astrocytes.
• Pharmacological manipulation of receptors and signaling pathways (muscarinic, metabotropic glutamate, IP3R2, TNF, TNFR1, GluN2B).

Main Results:

• SO priming stimulation inhibited LTP induction in the DG middle molecular layer (MML) synapses, demonstrating transregional metaplasticity.
• This effect occurred across the hippocampal fissure, independent of CA3, indicating reverse-direction, long-distance crosstalk.
• Astrocyte calcium signaling in the DG MML increased upon SO priming, and blocking this calcium signaling prevented the metaplasticity effect.
• The metaplasticity was triggered by M1 muscarinic or group II mGluR activation, dependent on IP3R2 signaling.
• Astrocytic tumor necrosis factor (TNF) release, acting on TNF type 1 receptors (TNFR1s), mediated the LTP inhibition via GluN2B-containing NMDA receptors.

Conclusions:

• A novel form of long-distance, transregional metaplasticity exists between hippocampal subregions (SO and DG MML).
• Astrocytes play a crucial role in mediating this metaplasticity through calcium signaling and TNF release.
• This neuron-glia signaling cascade involves specific receptor and signaling pathways, highlighting a complex regulatory mechanism for hippocampal plasticity.