Spreading Depression Promotes Astrocytic Calcium Oscillations and Enhances Gliotransmission to Hippocampal Neurons

Abstract

Spreading depression (SD) is a pathophysiological phenomenon characterized by propagating waves of profound neuronal and glial depolarization in central nervous system gray matter. Although SD is primarily mediated by neurons with a subsequent astrocytic response, it remains unclear how astrocytic activity is modulated after SD and how altered astrocyte signaling contribute to neuronal excitability. Here, we report that after the concurrent Ca²⁺ wave, SD enhanced astrocytic activity by promoting a secondary period of Ca²⁺ oscillations. SD-induced Ca²⁺ oscillations did not require the activation of metabotropic glutamate receptors or purinergic receptors; instead, they were mediated by the activation of GABA_B receptors and 1,4,5-trisphosphate (IP₃) receptors. Furthermore, SD increased the number of NMDA receptor-mediated slow inward currents (SICs) in CA1 pyramidal neurons. The frequency of SD-induced SICs was reduced by blockade of GABA_B receptors or by limiting Ca²⁺ efflux from the ER. Selective inhibition of astrocytic Ca²⁺ signals by dialysis of BAPTA into astrocytes or by knocking out the astrocytic type of IP₃ receptors suppressed SICs after SD. These results demonstrated a causative link between the SD-induced Ca²⁺ oscillations and the enhanced glutamatergic astrocyte-neuron signaling. Therefore, we conclude that SD enhances the astrocyte Ca²⁺ signals and further promotes gliotransmission and neuronal excitability.

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