1540-P: LRP1 in GABAergic Neurons Is a Key Link between Obesity and Memory Function

Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, and its dysfunction has been linked to cognitive decline, dementia, and Alzheimer’s disease. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in obesity remains unexplored. Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1^loxP/loxP) are subjected to conduct behavioral tests of locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. We evaluated the relationships between behavior outcomes and metabolic risk factors. Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function. In the spatial Y-maze test, Vgat-Cre; LRP1^loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1^loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice had a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in the contextual and cued fear conditioning tests, accompanied by increased neuronal necrosis and neuroinflammation in the hippocampus. Importantly, these memory deficits correlate negatively with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. Our findings demonstrate that LRP1 from GABAergic neurons is important in maintaining normal memory function. Metabolically, obesity caused by LRP1 deletion in GABAergic neurons negatively regulates memory and cognitive function. Thus, LRP1 in GABAergic neurons emerges as a key link between obesity and memory function, emphasizing its potential significance in maintaining neural system integrity associated with metabolism.