Β2-ADRENERGIC RECEPTOR-DEPENDENT ASTROCYTIC LACTATE SIGNALING IS REQUIRED FOR RECOGNITION MEMORY IN MICE

Recognition memory is a core cognitive function that enables the discrimination of familiar and novel stimuli and relies on coordinated processes in the brain. The noradrenergic (NA) system plays a critical role in memory formation through activation of β2-adrenergic receptors (β2-AR) expressed in neurons and astrocytes. In astrocytes, NA stimulates lactate production via lactate dehydrogenase A (LDHA), which is transported to neurons through monocarboxylate transporters (MCT), particularly MCT2, to support synaptic plasticity. However, the contribution of this pathway to recognition memory remains poorly understood. Here, we tested the hypothesis that NA modulation of recognition memory depends on astrocyte-derived lactate signaling. To address this, we conducted complementary in vitro and in vivo experiments. Lactate levels were measured in cultured astrocytes treated with vehicle, NA, the MCT blocker 4-CIN, or NA combined with the β2-AR antagonist butaxamine. Recognition memory was assessed using the Novel Object Recognition (NOR) task in mice. In one experiment, mice received vehicle, the NA reuptake inhibitor atomoxetine (ATO), or ATO combined with 4-CIN. In a second experiment, animals were treated with vehicle, the β2-AR antagonist ICI-118,551 (ICI), or ICI combined with exogenous lactate. LDHA and MCT2 expression levels were quantified by Western blot. Our results show that astrocytic lactate production is mediated by β2-AR activation. ATO enhanced NOR performance, an effect abolished by MCT blockade. Conversely, β2-AR antagonism impaired recognition memory, while lactate administration rescued this deficit. These findings demonstrate that β2-AR–dependent astrocytic lactate signaling is essential for recognition memory formation.
Funding: UJI-B2021-28;GACUJIMB/2024/01