Available online 16 April 2024, 101941

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GABAergic LRP1 plays an important role in learning and memory

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Loss of LRP1 from GABAergic neurons causes neurodegeneration in the hippocampus

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Impaired cognitive function is correlated with obesity-linked metabolic parameters

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LRP1 in GABAergic neurons is required for normal neural system integrity

AbstractObjective

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.

Keywords

LRP1

GABAergic neuron

Obesity

Behavior

Memory

Neurodegeneration

AbbreviationsLRP1

low-density lipoprotein receptor-related protein-1

LDL

low-density lipoprotein

HMS

Harvard Medical School

Vgat

vesicular GABA transporter

ELISA

enzyme linked immunosorbent assay

HOMA-IR

homeostatic model assessment for insulin resistance

APP

amyloid precursor protein

NOS2

nitric oxide synthase 2

NLRP3

nucleotide-binding domain

leucine-rich–containing family

pyrin domain–containing-3

SOCS3

suppressor of cytokine signaling 3

CCL2

chemokine (C-C motif) ligand 2

CX3CL1

C-X3-C motif chemokine ligand 1

AIF-1

Allograft inflammatory factor 1

CD68

cluster of differentiation 68

CD11b

cluster of differentiation molecule 11B

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

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

© 2024 The Author(s). Published by Elsevier GmbH.