Astrocytic GAT-3 inhibition disrupts memory formation by impairing protein synthesis and reducing Arc levels

Astrocytes regulate synaptic function through bidirectional communication with neurons. They respond to neurotransmitters, mediate uptake, and release gliotransmitters. GABA, the main inhibitory neurotransmitter in the CNS, controls neuronal excitability. Astrocytes primarily express GABA transporter 3 (GAT-3), which helps terminate GABAergic signaling and maintain neuronal homeostasis. We investigated the role of hippocampal GAT-3 in spatial memory consolidation and expression. Rats were trained in a spatial object recognition (SOR) task that induces long-term memory, and SNAP-5114 (SNAP), a selective GAT-3 inhibitor, was infused into the dorsal hippocampus around either training or test. SNAP impaired both memory consolidation and expression, whereas exposure to a novel open field (OF) rescued these deficits. Additionally, SNAP significantly reduced protein synthesis to levels comparable to emetine, a general protein synthesis inhibitor, as shown by the SUnSET assay. SNAP also decreased activity-regulated cytoskeleton-associated protein (Arc), a plasticity-related protein required for memory formation. Conversely, novel OF exploration increased Arc levels, suggesting that the rescue of SNAP-induced memory impairment involves protein synthesis-dependent mechanisms. These findings reveal a specific role for hippocampal GAT-3 in spatial memory and support astrocyte-dependent GABAergic regulation as a key mechanism in memory, with relevance to neurological disorders.