Estradiol Mediates Astrocyte-Neuron Communication in the Hippocampus

Accumulating evidence has revealed the existence of functional astrocyte-neuron communication based on the ability of astrocytes to respond to neurotransmitters and release gliotransmitters. However, little is known about how other signaling molecules, such as hormones, impact astrocyte function. Estradiol (E2) is an important hormone known to regulate neuronal activity, synaptic transmission, plasticity, and animal behavior. However, whether E2 specifically signals to astrocytes in situ and the functional consequences on astrocyte-neuron communication remain unknown. Therefore, we investigated the impact of estradiol on astrocyte activity and astrocyte-neuron communication in the mouse hippocampus. Using an RNAscope approach, we determined that estrogen receptors (ERα and ERβ) are expressed in astrocytes in both female and male mice. In both sexes, confocal imaging of hippocampal slices determined that astrocytes respond to locally applied E2 with calcium elevations. In pyramidal neurons, slow inward currents (SICs) are mediated by the activation of extrasynaptic NMDA receptors and indicate gliotransmission. Electrophysiological recordings of hippocampal neurons determined that E2 increases the frequency, but not the amplitude, of SICs. We also recorded excitatory synaptic transmission evoked by Schaffer collateral stimulation. Here, only in females, did E2 produce a reduction in excitatory synaptic transmission. The E2-induced effects on the astrocyte calcium signal and gliotransmission were prevented by the broad estrogen receptor antagonist ICI 182,780. Taken together, these results demonstrate the existence of estradiol-mediated astrocyte-neuron communication in both female and male mice. They reveal that E2 can signal to astrocytes and, through this signaling, E2 may regulate neuronal activity and synaptic transmission.