Vldlr overexpression causes hyperactivity in rats

Keiko Iwata,Tomoyasu Wakuda,Takayuki Manabe,Hideo Matsuzaki,Yukiko Ishibashi,Mahesh Mundalil Vasu,Katsuaki Suzuki,Ayyappan Anitha,Kazuo Yamada,Ismail Thanseem,Taro Takahashi,Yukio Ichitani,Nobuo Izumo,Chie Shimmura,Kazuhiko Nakamura,Yosuke Kameno,Norio Mori,Yasuhide Iwata

doi:10.1186/2040-2392-3-11

Abstract

BackgroundReelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients.MethodsWe generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.ResultsSpontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function.ConclusionsUnlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities.

Highlights

Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors verylow-density lipoprotein receptor (Vldlr) and lipoprotein receptor-related protein 8 (Lrp8)
Generation of Vldlr transgenic rats To evaluate the effects of increasing Vldlr expression in rats, we generated Tg rats harboring a Sal I/Bsa BI fragment from the expression vector pCX-Vldlr-internal ribosome entry site (IRES)-enhanced green fluorescent protein (EGFP) (Figure 1A)
Vldlr protein was strongly detected in line 1 pups, whereas the expression was very weak in line 2 and 3 pups (Figure 1C)

Summary

Introduction

Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports implicate reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression [27,28,29,30,31,32,33,34,35]. Post-mortem studies have reported decreased levels of reelin and its message in patients with autism, schizophrenia, and bipolar disorder, with less consistent findings for depression [27,29,30,32,33,36]. Homozygous reeler mutant mice are characterized by ataxia, tremors, imbalance, and a reeling gait, associated with severe hypoplasia of the cerebellum and neuronal ectopia in laminated brain regions [2]. Heterozygous mice do not show obvious defects: two detailed studies have reported no defects in the behavioral phenotype of heterozygous mice [37,38], a subsequent study reported deficits in contextual fear conditioning [39]

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Discussion

Conclusion