GABAergic LRP1 is a key link between obesity and memory function

Objective Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Loss of LRP1 from inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. Its dysfunction has been associated with cognitive decline, dementia, and Alzheimer’s disease. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. Methods Mice lacking LRP1 in GABAergic neurons ( Vgat-Cre; LRP1loxP/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 and metabolic risk factors. Results Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls ( LRP1loxP/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 these mice when the contextual and cued fear conditioning tests were conducted. These effects were accompanied by increased neuronal necrosis and neuroinflammation in the hippocampus. Importantly, the distance and duration in the novel arm and the performance of the reversal water T-maze test negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. Conclusions Our findings demonstrate that LRP1 from GABAergic neurons is important in normal memory function. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance and impacts memory function, reinforcing the potential importance of LRP1 in neural system integrity. ### Competing Interest Statement The authors have declared no competing interest. * ### Abbreviations LRP1 : low-density lipoprotein receptor-related protein-1; LDL : low-density lipoprotein; Aβ : amyloid beta; HMS : Harvard Medical School; Vgat : vesicular GABA transporter; ELISA : enzyme linked immunosorbent assay; HOMA-IR : homeostatic model assessment for insulin resistance; PSEN1 : presenilin-1; APP : amyloid precursor protein; TBS : tris-buffered saline; H&E : hematoxylin and eosin; IHC : Immunohistochemistry; ABC : avidin–biotin–peroxidase complex; GFAP : glial fibrillary acidic protein; IBA1 : ionized calcium binding adaptor molecule 1; GAD67 : glutamic acid decarboxylase 67; DAB-H2O2 : 3,3’-diaminobenzidine tetrahydrochloride; AF : Alexa fluor; FFA : free fatty acids; ApoJ : apolipoprotein J; CCFC : contextual and cued fear conditioning tasks; NMDARs : N-methyl-d-aspartate receptors; GABA : gamma-aminobutyric acid; PBS : phosphate-buffered saline; ANOVA : analysis of variance