LRP1 in GABAergic neurons is a key link between obesity and memory function

Kellen Cristina da Cruz Rodrigues; Seung Chan Kim; Aaron Aykut Uner; Zhi-Shuai Hou; Jennie Young; Clara Campolim; Ahmet Aydogan; Brendon Chung; Anthony Choi; Won-Mo Yang; Woojin S. Kim; Vincent Prevot; Barbara J. Caldarone; Hyon Lee; Young-Bum Kim

Molecular Metabolism (Jun 2024)

LRP1 in GABAergic neurons is a key link between obesity and memory function

Kellen Cristina da Cruz Rodrigues,
Seung Chan Kim,
Aaron Aykut Uner,
Zhi-Shuai Hou,
Jennie Young,
Clara Campolim,
Ahmet Aydogan,
Brendon Chung,
Anthony Choi,
Won-Mo Yang,
Woojin S. Kim,
Vincent Prevot,
Barbara J. Caldarone,
Hyon Lee,
Young-Bum Kim

Affiliations

Kellen Cristina da Cruz Rodrigues: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Seung Chan Kim: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Aaron Aykut Uner: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Zhi-Shuai Hou: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Jennie Young: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Clara Campolim: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Ahmet Aydogan: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Brendon Chung: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Anthony Choi: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Won-Mo Yang: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Woojin S. Kim: The University of Sydney, Brain and Mind Centre & School of Medical Sciences, Sydney, NSW, Australia
Vincent Prevot: University of Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, Lille, France
Barbara J. Caldarone: Mouse Behavior Core, Department of Genetics, Harvard Medical School, Boston, MA, USA
Hyon Lee: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
Young-Bum Kim: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA; Corresponding author. Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215 USA.

Journal volume & issue: Vol. 84
p. 101941

Abstract

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Objective: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood–brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. 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) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. Results: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. 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 showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. Conclusions: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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