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 long been shown as necessary for physiological synaptic function, the role of astroglial TNFR2 was never explored. Here, we show 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., upregulation of SNARE complex molecules, glutamate receptor subunits, glutamate transporters) essential for hippocampal synaptic transmission and plasticity. This was most evident in male mice compared to females. In the hippocampus, Gfap(creERT2):Tnfrsf1b(fl/fl) male mice but not females showed elevated numbers of astrocytes and microglia, as well as increased glial reactivity measured by TSPO autoradiography. These cellular alterations ultimately translated into functional deficits, specifically learning and memory impairments measured by novel object recognition and Morris water maze tests, and suppressed long-term potentiation (LTP). Finally, RNA sequencing of sorted hippocampal astrocytes showed that, in Gfap(creERT2):Tnfrsf1b(fl/fl) male mice, genes and pathways implicated in synaptic plasticity as well as astrocyte-neuron and astrocyte-oligodendrocyte communication were downregulated compared to Tnfrsf1b(fl/fl) control mice. Together, our findings indicate that TNFR2 signaling in astrocytes is essential for proper astrocyte-neuron communication at the basis of synaptic function, and that this mechanism is regulated in a sex-dependent manner.