Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation

Significance Experiences are remembered long-term when these memories are formed in a state of arousal and heightened emotion. The arousal-induced release of noradrenaline is critical for modulating consolidation, the process that establishes long-term memory. Although the effects of pharmacological manipulation of adrenergic signaling on memory stability are already being investigated in the clinical setting, how adrenergic receptors mediate long-term memory consolidation remains unclear. This study reports a previously unidentified mechanism with important translational implications: The noradrenergic receptors that in the hippocampus mediate memory consolidation are β2-adrenergic receptors (β2ARs) expressed in astrocytes. These receptors are necessary for the learning-evoked release of lactate from astrocytes, which then is required to support the neuronal molecular changes essential for long-term memory formation. Emotionally relevant experiences form strong and long-lasting memories by critically engaging the stress hormone/neurotransmitter noradrenaline, which mediates and modulates the consolidation of these memories. Noradrenaline acts through adrenergic receptors (ARs), of which β2-adrenergic receptors (βARs) are of particular importance. The differential anatomical and cellular distribution of βAR subtypes in the brain suggests that they play distinct roles in memory processing, although much about their specific contributions and mechanisms of action remains to be understood. Here we show that astrocytic rather than neuronal β2ARs in the hippocampus play a key role in the consolidation of a fear-based contextual memory. These hippocampal β2ARs, but not β1ARs, are coupled to the training-dependent release of lactate from astrocytes, which is necessary for long-term memory formation and for underlying molecular changes. This key metabolic role of astrocytic β2ARs may represent a novel target mechanism for stress-related psychopathologies and neurodegeneration.

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