Hippocampal astrocytic GAT-3 blockade impairs protein synthesis and spatial memory dynamics

Astrocytes are essential components of the tripartite synapse, where they modulate synaptic function and plasticity. One key mechanism involves GABA transporter GAT-3, primarily expressed in astrocytes, which helps terminate GABAergic signaling and maintain synaptic homeostasis. We studied the role of hippocampal GAT-3 in spatial memory dynamics using the spatial object recognition (SOR) task in female Wistar rats. GAT-3 inhibition with SNAP-5114 (SNAP) in the dorsal hippocampus impaired memory consolidation without affecting acquisition. This deficit was rescued by prior open field (OF) exposure, and blocked by the protein synthesis inhibitor emetine, indicating that astrocytic GAT-3 influences consolidation via protein synthesis mechanisms. Similarly, pre-treatment with the proteasome inhibitor β-Lactacystin mitigated SNAP-induced deficits. Puromycin incorporation assays confirmed that SNAP reduced hippocampal protein synthesis. Additionally, SNAP administration before memory retrieval impaired expression, which was also rescued by OF exposure or β-Lactacystin infusion. In contrast, SNAP did not affect reconsolidation, a process impaired by Nipecotic Acid administration, a broader GABA transporter inhibitor. These findings reveal that GAT-3 function modulates memory consolidation and expression, but not its reconsolidation, and also is involved in the regulation of protein synthesis level. Our results highlight astrocytic GABA transport as a critical determinant of spatial memory regulation and a potential contributor to cognitive dysfunction in neurological disorders.