Loss of LRP1 from GABAergic neurons impairs short-term memory function

Abstract

AbstractLow-density lipoprotein receptor-related protein-1 (LRP1) plays an important role in regulating energy homeostasis, the integrity of the blood-brain barrier, and metabolic signal transport across the brain, while its dysfunction has been associated with cognitive decline, dementia, and Alzheimer’s disease. However, the impact of LRP1 in GABAergic neurons on neurodegeneration and memory is poorly understood. Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) were subjected to behavioral tests for memory and learning. Here we show that the loss of LRP1 in GABAergic neurons causes significant impairment in short-term memory. The spatial Y-maze test revealed that Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared to the controls (LRP1loxP/loxP mice). A reduction in correct responses to find the escape platform in the water T-maze test was found when LRP1 is absent in GABAergic neurons. Moreover, the distance and duration in the novel arm as well as the performance of the reversal water T-maze test were negatively correlated with body weight as well as serum levels of leptin, insulin, and ApoJ. Mice lacking LRP1 in GABAergic neurons displayed decreased freezing time in the contextual and cued fear conditioning test. Histopathological evaluation of the hippocampus revealed that Vgat-Cre; LRP1loxP/loxP mice had greater neuronal necrosis and neuroinflammation than those of LRP1loxP/loxP mice. These findings suggest that LRP1 in GABAergic neurons may play a crucial role in maintaining normal memory function and could be a molecular target for neurodegenerative diseases such as Alzheimer’s disease.