TNFα Controls Glutamatergic Gliotransmission in the Hippocampal Dentate Gyrus

Glutamatergic gliotransmission provides a stimulatory input to excitatory synapses in the hippocampal dentate gyrus. Here, we show that tumor necrosis factor-alpha (TNF alpha) critically controls this process. With constitutive TN Fa present, activation of astrocyte P2Y1 receptors induces localized [Ca2+](i) elevations followed by glutamate release and presynaptic NMDA receptor-dependent synaptic potentiation. In preparations lacking TNF alpha, astrocytes respond with identical [Ca2+](i) elevations but fail to induce neuro-modulation. We find that TNF alpha specifically controls the glutamate release step of gliotransmission. In cultured astrocytes lacking TNF alpha glutamate exocytosis is dramatically slowed down due to altered vesicle docking. Addition of low picomolar TNF alpha promptly reconstitutes both normal exocytosis in culture and gliotransmission in situ. Alternatively, gliotransmission can be re-established without adding TNF alpha, by limiting glutamate uptake, which compensates slower release. These findings demonstrate that gliotransmission and its synaptic effects are controlled not only by astrocyte [Ca2+](i) elevations but also by permissive/homeostatic factors like TNF alpha.