Astroglial TNFR2 signaling regulates hippocampal synaptic function and plasticity in a sex dependent manner

Astrocytes participate in synaptic transmission and plasticity through tightly regulated, bidirectional communication with pre- and post-synaptic neurons, as well as microglia and oligodendrocytes. A key component of astrocyte-mediated synaptic regulation is the cytokine tumor necrosis factor (TNF). TNF signals via two cognate receptors, TNFR1 and TNFR2, both expressed in astrocytes. While TNFR1 signaling in astrocytes has been long demonstrated to be necessary for physiological synaptic function, the role of astroglial TNFR2 has never been explored. Here, we demonstrate that astroglial TNFR2 is essential for maintaining hippocampal synaptic function and plasticity in physiological conditions. Indeed, Gfap ^creERT2 :Tnfrsf1b ^fl/fl mice with selective ablation of TNFR2 in astrocytes exhibited dysregulated expression of neuronal and glial proteins (e.g., SNARE complex molecules, glutamate receptor subunits, glutamate transporters) essential for hippocampal synaptic transmission and plasticity. Hippocampal astrocytes sorted from Gfap ^creERT2 :Tnfrsf1b ^fl/fl mice displayed downregulation of genes and pathways implicated in synaptic plasticity, as well as astrocyte-neuron and astrocyte-oligodendrocyte communication. These alterations were accompanied by increased glial reactivity and impaired astrocyte calcium dynamics, and ultimately translated into functional deficits, specifically impaired long-term potentiation (LTP) and cognitive functions. Notably, male Gfap ^creERT2 :Tnfrsf1b ^fl/fl mice exhibited more pronounced hippocampal synaptic and cellular alterations, suggesting sex-dependent differences in astroglial TNFR2 regulation of synaptic function. Together, these findings indicate that TNFR2 signaling in astrocytes is essential for proper astrocyte-neuron communication at the basis of synaptic function, and that this is regulated in a sex-dependent manner.