SREBP-1c Deficiency Affects Hippocampal Micromorphometry and Hippocampus-Dependent Memory Ability in Mice.

Mary Jasmin Ang,Changjong Moon,Tae-Il Jeon,Poornima D E Weerasinghe-Mudiyanselage,Mai Wada,Sueun Lee,Sung-Ho Kim,Taekyun Shin,Seung-Soon Im

doi:10.3390/ijms22116103

Abstract

Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration of novel modulatory molecules in the hippocampus and occurrence of schizophrenia-like behaviors in mice. However, the possible underlying mechanisms, related to neuronal plasticity in the hippocampus, are yet to be elucidated. In this study, we investigated the hippocampus-dependent memory function and neuronal architecture of hippocampal neurons in SREBP-1c knockout (KO) mice. During the passive avoidance test, SREBP-1c KO mice showed memory impairment. Based on Golgi staining, the dendritic complexity, length, and branch points were significantly decreased in the apical cornu ammonis (CA) 1, CA3, and dentate gyrus (DG) subregions of the hippocampi of SREBP-1c KO mice, compared with those of wild-type (WT) mice. Additionally, significant decreases in the dendritic diameters were detected in the CA3 and DG subregions, and spine density was also significantly decreased in the apical CA3 subregion of the hippocampi of KO mice, compared with that of WT mice. Alterations in the proportions of stubby and thin-shaped dendritic spines were observed in the apical subcompartments of CA1 and CA3 in the hippocampi of KO mice. Furthermore, the corresponding differential decreases in the levels of SREBP-1 expression in the hippocampal subregions (particularly, a significant decrease in the level in the CA3) were detected by immunofluorescence. This study suggests that the contributions of SREBP-1c to the structural plasticity of the mouse hippocampus may have underlain the behavioral alterations. These findings offer insights into the critical role of SREBP-1c in hippocampal functioning in mice.

Highlights

Alterations in neuronal structure and function have been implicated in the pathophysiology of various neurological disorders [1]
We observed that Sterol regulatory element-binding protein (SREBP)-1c KO mice had altered behaviors suggestive of the positive and negative symptoms of schizophrenia, but not its cognitive symptoms
We previously reported schizophrenia-like behavior and altered hippocampal gene expressions in SREBP-1c-deficient mice

Summary

Introduction

Alterations in neuronal structure and function have been implicated in the pathophysiology of various neurological disorders [1]. The hippocampus is one of the few remaining regions capable of undergoing neuronal plasticity even during adulthood, rendering it especially susceptible to structural and functional alterations [2,3]. These hippocampal alterations further translate to abnormalities of emotions, learning, and memory [4]. SREBPs are transcription factors, controlling both cholestero- and lipogenesis, via the activation of enzymatic cascades required for the synthesis of endogenous cholesterol, fatty acids, and triglycerides [14]. There is a commonality in their activities, SREBP-1c favors the control of fatty acid and triglyceride synthesis, while SREBP-2 mainly regulates cholesterol synthesis and SREBP-1a does not display any particular preference [13]

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Conclusion