Astrocytic H3 receptors regulate anxiety through GABA signaling

Abstract

Anxiety disorders are the most prevalent mental disorders globally, yet current treatments remain limited. Histamine is an evolutionarily conserved neuromodulator recently implicated in neuropsychiatric disorders. However, whether and how histaminergic signaling dynamically represents emotionally salient information and regulates anxiety remain largely unknown. We show that anxiogenic exposure triggers region-specific dynamic histamine release in ventral hippocampal CA1 (vCA1). The vCA1-projecting histaminergic circuit exhibits similar dynamics and bidirectionally regulates anxiety through engaging astrocytic H3 receptors (H3Rs). Genetic ablation of astrocytic H3Rs attenuates astrocytic responsiveness to anxiety-related contexts and directly promotes anxiety via gliotransmitter γ-aminobutyric acid (GABA) signaling. Notably, chronic stress induces adaptive upregulation of vCA1 astrocytic H3R expression, while further potentiation of astrocytic H3R signaling is sufficient to attenuate maladaptive anxiety. These findings collectively establish that vCA1 astrocytic histaminergic signaling governs natural anxiolysis in both normal and maladaptive anxiety states, identifying astrocytic H3Rs as crucial emotional regulators and a potential therapeutic target for anxiety disorders.

Keywords: GABA; H3 receptors; anxiety disorders; astrocyte; histamine.