Vldlr overexpression causes hyperactivity in rats
- Keiko Iwata†1,
- Nobuo Izumo†2,
- Hideo Matsuzaki1Email author,
- Takayuki Manabe3,
- Yukiko Ishibashi4,
- Yukio Ichitani5,
- Kazuo Yamada5,
- Ismail Thanseem6,
- Ayyappan Anitha1,
- Mahesh Mundalil Vasu6,
- Chie Shimmura6,
- Tomoyasu Wakuda6,
- Yosuke Kameno6,
- Taro Takahashi1,
- Yasuhide Iwata6,
- Katsuaki Suzuki1,
- Kazuhiko Nakamura6 and
- Norio Mori6
© Iwata et al.; licensee BioMed Central Ltd. 2012
Received: 20 June 2012
Accepted: 26 September 2012
Published: 30 October 2012
Reelin 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.
We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.
Spontaneous 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.
Unlike 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.
KeywordsHyperactivity Neurodevelopmental disorder Psychiatric disorder Reelin Transgenic rat Vldlr
Reelin, a large secreted glycoprotein, is critical for normal brain development [1–3]. During embryonic development, reelin is secreted by specialized Cajal-Retzius cells to form a highly laminated structure in the neocortex, hippocampus, and cerebellum [2, 4–6]. The reelin signaling pathway involves two reelin receptors, very-low-density lipoprotein receptor (Vldlr) and low-density lipoprotein receptor-related protein 8 (Lrp8), and the intracellular adaptor protein, disabled homolog 1 (Dab1) [7–9].
A number of studies have reported that reelin signaling is involved in the dopaminergic system, especially the expression of dopamine receptors in the nucleus accumbens [10, 11]. Moreover, considerable evidence has implicated nucleus accumbens dopamine in the regulation of locomotor activity [12–17]. Additionally, recent studies have demonstrated the necessity for reelin signaling in certain aspects of hippocampal synaptic function, the formation of some forms of mammalian memory, and cognitive function [18–26].
Several reports implicate reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression [27–35]. 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]. The finding of reduced reelin levels in these disorders has prompted interest in the reeler mutant mouse, which has a spontaneous mutation in the reelin gene, as an animal model of neurodevelopmental and psychiatric disorders. 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 . Owing to the severe gait defects, it is difficult to evaluate other behavioral phenotypes. Heterozygous mice do not show obvious defects: two detailed studies have reported no defects in the behavioral phenotype of heterozygous mice [37, 38], although a subsequent study reported deficits in contextual fear conditioning .
Fatemi et al. reported that post-mortem VLDLR mRNA levels are increased in the brain of autistic patients . Furthermore, it has been reported that psychotropic drug treatment changes Vldlr expression in the rat brain . However, little attention has been given to increased Vldlr expression. In this study, we generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.
All experiments were approved by the Committee on Animal Research of Hamamatsu University School of Medicine, Yokohama College of Pharmacy and University of Tsukuba. All experiments were performed in accordance with the Guide for Animal Experimentation at the Hamamatsu University School of Medicine, Yokohama College of Pharmacy and University of Tsukuba.
Generation of Vldlr transgenic rats
RNA isolation and quantitative real-time reverse-transcription-polymerase chain reaction
Total RNA was isolated from whole brain or specific brain regions, using TRIZOL Reagent (Invitrogen, Carlsbad, CA), and reverse transcribed using the SuperScript III First-Strand Synthesis System (Invitrogen). cDNA was used for qRT-PCR, which was performed using the SYBR GREEN PCR Master Mix (Qiagen, Hilden, Germany). Actb expression was used as a control for mRNA expression. Gene expression changes were quantified using the delta-delta CT method. The primer sequences were as follows: Vldlr sense, 5′-TTCACATCCTCCATTCTCCA-3′; antisense, 5′-CAATCTCAATGATGCCCAAG-3′; Dab1 sense, 5′-GCTTTGAAAGTCCCAGCAAG-3′; 5′-antisense, ATGGATCACTGGTGGAGGAG-3′; Actb sense, 5′-CGTGAAAAGATGACCCAGATCA-3′; antisense, 5′-AGAGGCATACAGGGACAACACA-3′.
Rat livers were dissected in 0.9% NaCl at postnatal day 0 (P0). Tissues were placed in ice-cold homogenization buffer containing 0.32 M sucrose, 3 mM HEPES (pH 7.3) and a protease inhibitor Complete Mini tablet (Roche Diagnostics, Mannheim, Germany), for homogenization. Total lysates were centrifuged at 1,000g for 10 min at 4°C. The supernatants were collected and centrifuged at 20,000g for 30 min at 4°C. The pellets, containing the membrane fractions, were resuspended in 10% sodium dodecyl sulfate (SDS). The protein concentration in the membrane fractions was measured and normalized to 10% SDS.
Western blot analysis
Membrane fractions (70 μg) were subjected to 7.5% SDS-polyacrylamide gel electrophoresis, followed by blotting to a polyvinylidene fluoride membrane (GE Healthcare, Little Chalfont, UK). The transferred membranes were incubated with a primary antibody against Vldlr (1:200; 6A6, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) or β-actin (1:4,000; Abcam, Inc., Cambridge, MA) at 4°C overnight. After incubation, the membranes were washed three times with phosphate-buffered saline without Mg2+ or Ca2+ (PBS(−)), containing 0.1% Tween-20, and were then incubated with the appropriate secondary antibody (1:20,000) at room temperature for 1 h. The membranes were washed with PBS(−) containing 0.1% Tween-20, followed by visualization using an enhanced chemiluminescence system (ECL plus; GE Healthcare).
Rats were anesthetized and perfused with 4% paraformaldehyde in PBS(−). The brains were removed and postfixed in the same fixative at 4°C, then transferred to 30% sucrose in PBS(−). When they sank, the brains were embedded in OCT compound (Tissue Tek, Sakura Finetek USA Inc., Torrance, CA) and frozen on powdered dry ice. Serial sections (30 μm) were cut and floated in PBS(−). The first series sections were stained with cresyl violet for Nissl staining. The second series sections were incubated overnight at 4°C with anti-neuronal nuclei (NeuN) antibody (mouse monoclonal IgG, 1:500; Millipore, Ltd., Watford, UK). The sections were then washed and incubated with biotin-conjugated anti-mouse IgG (1:200, Vector Laboratories, Burlingame, CA) for 1 h at room temperature. After washing, the sections were processed for 1 h using a Vectastain ABC kit (Vector Laboratories). Staining was visualized with diaminobenzidine (Vector Laboratories) as the chromatic agent. Control slices were incubated as described, but without primary antibody. No immunoreactivity was seen in the controls (data not shown).
The open-field test is one of the best established ways to test exploratory locomotor activity in a novel environment. A square open field (90 cm × 90 cm) was constructed from gray polyamide enclosed by a 40 cm high surrounding wall. Each open field was divided into central (30 cm × 30 cm) and outer areas. The 15-min test was started after placing each rat individually in the same corner facing the wall. Behavior was recorded, and distance traveled (cm) and time spent in the central area (s) were analyzed, using the video-tracking system Viewer (version 2.2; Neuroscience, Inc., Tokyo, Japan).
Spontaneous locomotor activity test
To measure spontaneous locomotor activity, a rat was placed in a plastic cage (24.5 cm × 40 cm × 20 cm) with clean paper, food, and water. To ensure that the novelty of the cage did not confound the activity measurements, the first 17 hours of activity were not analyzed. Locomotion was measured per hour throughout the whole day using a digital counter with an infrared sensor (NS-AS01; Neuroscience, Inc.). The room light was on from 7:00 a.m. to 7:00 p.m.
Radial maze test
This test used an elevated eight-arm radial maze made of black polyvinyl chloride. The maze consisted of an octagonal central platform (32 cm in diameter) and eight arms (60 cm × 12 cm) radiating from the platform. A food well (1 cm in diameter, 0.5 cm deep) was carved out at the end of each arm. Plexiglas guillotine doors (15 cm high) divided the arms from the central platform, and each was operated automatically. The sidewalls of the arms were 4 cm high, except 12 cm from guillotine doors, where they were 12 cm high. The maze was elevated 70 cm above the floor. There were extra-maze visual cues (for example, a curtain, a desk, colored drawing paper, and a door) around the maze. Control and analysis of the behavioral experiment was carried out using Image RM (O’Hara Co., Ltd, Tokyo, Japan), a modified version of the free software NIH Image (National Institutes of Health, Bethesda, MD).
Rats were given 5 min handling for three days and then three daily sessions of habituation to the apparatus. In the habituation session, all the guillotine doors were opened and 20 mg food pellets (Research Diets, Inc., New Brunswick NJ) were placed on the platform and arms. In the first two sessions, five rats were placed in the maze together for 30 min, and in the last session, each rat was placed in the maze individually for 15 min. Rats were trained on the radial maze task for one trial a day. At the beginning of each trial, a 20 mg food pellet was placed in each food well. The rat was placed on the central platform and all the doors were opened. A choice was counted when the rat completely entered an arm; then all the doors except that of the chosen arm were closed. When the rat returned to the central platform, the door was closed and the rat confined there for 5 s. After that, all the doors were reopened and the rat was allowed the next choice. This procedure was repeated until the animal had consumed all the pellets, it had made 16 choices, or 10 min had elapsed since the start of the trial. A correct choice was defined when the rat entered an arm that had not previously been entered during the trial or in which the pellet had not been consumed; the other choices were counted as errors. The learning criterion was defined as five consecutive trials in which seven or more correct choices, in the first eight choices, were attained. The rats’ choice responses were recorded.
Social interaction test
Social interaction was tested in the same apparatus used for the open-field test. Each rat was tested for 15 min with a weight-matched partner from a different home cage. Social interaction was assessed by the time spent interacting, including sniffing, following, crawling over or under, grooming, and aggressive behaviors.
Elevated plus maze test
The elevated plus maze is a well-established model to assess the level of anxiety in rodents. The apparatus was made of gray polyamide and comprised two open arms (50 cm × 9 cm), two enclosed arms (50 cm × 9 cm × 50 cm), and a central platform (8.5 cm × 8.5 cm). The apparatus was elevated 50 cm above the floor. At the beginning of the test, the rats were placed on the central platform facing the same open arm. The test lasted 10 min and the behavior of the rat was recorded; the time spent in the closed and open arms was analyzed by a video-tracking system, as described.
Statistical significance of Vldlr and Dab1 mRNA levels were analyzed using unpaired Student’s t tests, after it had been confirmed that there were no statistically significant differences in variance, as assessed by the F test. Repeated measures analyses of variance (ANOVA) and unpaired Student’s t tests were used for analysis of the behavioral tests.
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-IRES-EGFP (Figure 1A). Three transgenic founders were identified by PCR and whole-body EGFP fluorescence. The growth patterns of all founders and non-transgenic (wild-type, Wt) littermates were similar, indicating no severe effect of the Vldlr transgene in terms of growth of the Tg rats. All founders gave rise to true-breeding lines (lines 1, 2, and 3), and transmitted the transgene and EGFP fluorescence to their offspring. Both males and females reproduced at a rate similar to that of their Wt littermates, and their offspring grew normally.
First, we examined whether exogenous Vldlr was expressed at the plasma membrane in Tg rats. Vldlr is not expressed endogenously in rat liver . Therefore, we collected membrane fractions from the livers of two pups, from each line, and examined Vldlr expression by Western blotting. Vldlr protein was strongly detected in line 1 pups, whereas the expression was very weak in line 2 and 3 pups (Figure 1C). Second, we confirmed overexpression of Vldlr mRNA in the whole brain by qRT-PCR. An approximately 1.5-fold increase in Vldlr mRNA was detected (Figure 1D) in line 1 Tg rats, compared with Wt rats, at P0 (P < 0.01). However, there was no significant increase in mRNA levels in lines 2 or 3. In line 1, Vldlr overexpression was detected in the adult (2 to 3 months) brain, at the same level as at P0 (P < 0.01; Figure 1E, upper graph). In addition, we measured Vldlr mRNA in multiple brain regions of relevance to autism, including the prefrontal cortex, hippocampus, and cerebellum, using adult rats. Vldlr expression levels were increased in these regions 1.3-, 1.2- and 1.6-fold, respectively, in Tg rats compared with Wt rats (P < 0.01, P < 0.05 and P < 0.01, respectively; Figure 1E, lower graphs). Thus, in transgenic line 1, Vldlr is stably overexpressed, including in brain regions relevant to autism. Finally, we investigated whether downstream signaling pathways are altered by Vldlr overexpression. The tyrosine residue of Dab1 is phosphorylated, following reelin binding to Vldlr . It has been suggested that Dab1 phosphorylation causes a reduction in Dab1 protein levels via a negative feedback circuit . Moreover, Fatemi et al. have reported increased VLDLR and reduced DAB1 mRNA levels in post-mortem brain tissue (prefrontal cortex area 9 and cerebellum) from patients with autism . Therefore, we measured Dab1 mRNA expression in the prefrontal cortex, hippocampus, and cerebellum of adult rats. In Tg rats, Dab1 expression levels were decreased in prefrontal cortex and cerebellum by 0.89- and 0.67-fold, respectively, compared with Wt rats (P < 0.05; Figure 2). However, there was no significant decrease in mRNA levels in the hippocampus, potentially driven by a reduced rate of Vldlr accumulation in hippocampus compared to prefrontal cortex or cerebellum. Overall, our results show that Vldlr overexpression changes downstream reelin signaling in Tg rats, at least in the prefrontal cortex and cerebellum. Moreover, Tg rats show abnormal expression of Vldlr and Dab1 mRNA, as detected in post-mortem brain from patients with autism. Based on our expression results, we chose transgenic line 1 for further analysis.
No abnormal brain morphology in Vldlr-Tg rats
Vldlr-Tg rats show hyperactivity and memory impairment
We have developed a rat model in which the Vldlr transgene is driven by a strong ubiquitous promoter, to test the in vivo neurological effects of Vldlr overexpression. Vldlr overexpression changed downstream reelin signaling in Tg rats, as determined by reduced Dab1 expression. Moreover, Tg rats showed abnormalities in Vldlr and Dab1 mRNA expression, similar to those detected in post-mortem brain from patients with autism . We found that spontaneous locomotor activity was significantly increased, and a tendency toward impaired memory function in Tg rats, without changes in histology.
In Vldlr knockout mice, the most remarkable histological phenotype is a smaller and less foliated cerebellum, with slight abnormalities found in the hippocampus and neuronal layers of the cerebral cortex . In contrast, in Vldlr-Tg rats, there were no histological abnormalities, even in the cerebellum. This suggests that a 1.5-fold increase in Vldlr may not be sufficient to affect brain morphology.
The mechanism for the hyperactivity in the Tg rats is unclear. It has been reported that the SH3-domain kinase binding protein 1 (Sh3kbp1), which is involved in receptor endocytosis, binds Dab1, a downstream molecule in reelin signaling. The resulting interaction may play a role in the endocytosis of reelin receptors including Vldlr, and cause downregulation of reelin signaling . Interestingly, Sh3kbp1 knockout mice display hyperactivity . Additionally, they display abnormally high levels of dopamine and D2 dopamine receptors in the striatum . Similarly, several studies have reported that reelin signaling is involved in dopamine receptor expression in the striatum [10, 11]. Although there has been no report of Vldlr expression in Sh3kbp1 knockout mice, it is feasible that membrane expression of Vldlr is upregulated, resulting in facilitation of the dopaminergic system and hyperactivity in the mice. This suggests that Vldlr regulates the dopaminergic system, and may cause the hyperactivity observed in the Tg rats.
The spontaneous social interaction test that we used in this study is a standard test used to measure social interaction between animals. Using this test enabled us to examine other social behaviors, such as aggression, without performing additional behavioral tests. In the course of our testing, we ascertained aggressive behavior, and found Vldlr-Tg rats not to be aggressive (data not shown). We did not apply other tests to measure social behavior, such as a social novelty test, in depth, so there remains the possibility that Vldlr-Tg rats may show differences in some domains of social behavior.
Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders [27–35]. However, patients with these disorders do not show striking neuroanatomical aberrations. For example, although post-mortem and structural magnetic resonance imaging have highlighted the frontal lobes, amygdala, and cerebellum as pathologically affected in autism, there is no clear and consistent pathology for this disorder . Notably, hyperactivity and working memory impairment are symptoms observed in neurodevelopmental and psychiatric disorders, including autism . Therefore, our findings of hyperactivity and memory impairment in Vldlr-Tg rats are significantly relevant, from a clinical point of view.
Disabled homolog 1
Enhanced green fluorescent protein
Internal ribosome entry site
Low-density lipoprotein receptor-related protein 8
Phosphate-buffered saline without Mg2+ or Ca2+
Quantitative reverse transcription-polymerase chain reaction
Sodium dodecyl sulfate
SH3-domain kinase binding protein 1
Very-low-density lipoprotein receptor
We thank Tae Takahashi, Mika Oyaizu and Erina Sakamoto for excellent technical assistance. This study was supported by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to NM), and a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to KI).
- Bar I, Lambert De Rouvroit C, Royaux I, Krizman D, Dernoncourt C, Ruelle D, Beckers M, Goffinet A: A YAC contig containing the reeler locus with preliminary characterization of candidate gene fragments. Genomics. 1995, 26: 543-549. 10.1016/0888-7543(95)80173-J.View ArticlePubMedGoogle Scholar
- D’Arcangelo G, Miao G, Chen S, Soares H, Morgan J, Curran T: A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature. 1995, 374: 719-723. 10.1038/374719a0.View ArticlePubMedGoogle Scholar
- Quattrocchi C, Wannenes F, Persico A, Ciafré S, D’Arcangelo G, Farace M, Keller F: Reelin is a serine protease of the extracellular matrix. J Biol Chem. 2002, 277: 303-309.View ArticlePubMedGoogle Scholar
- Aguiló A, Schwartz T, Kumar V, Peterlin Z, Tsiola A, Soriano E, Yuste R: Involvement of Cajal-Retzius neurons in spontaneous correlated activity of embryonic and postnatal layer 1 from wild-type and reeler mice. J Neurosci. 1999, 19: 10856-10868.PubMedGoogle Scholar
- Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K: The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron. 1995, 14: 899-912. 10.1016/0896-6273(95)90329-1.View ArticlePubMedGoogle Scholar
- Soda T, Nakashima R, Watanabe D, Nakajima K, Pastan I, Nakanishi S: Segregation and coactivation of developing neocortical layer 1 neurons. J Neurosci. 2003, 23: 6272-6279.PubMedGoogle Scholar
- D’Arcangelo G, Homayouni R, Keshvara L, Rice D, Sheldon M, Curran T: Reelin is a ligand for lipoprotein receptors. Neuron. 1999, 24: 471-479. 10.1016/S0896-6273(00)80860-0.View ArticlePubMedGoogle Scholar
- Hiesberger T, Trommsdorff M, Howell B, Goffinet A, Mumby M, Cooper J, Herz J: Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999, 24: 481-489. 10.1016/S0896-6273(00)80861-2.View ArticlePubMedGoogle Scholar
- Strasser V, Fasching D, Hauser C, Mayer H, Bock H, Hiesberger T, Herz J, Weeber E, Sweatt J, Pramatarova A, Howell B, Schneider W, Nimpf J: Receptor clustering is involved in reelin signaling. Mol Cell Biol. 2004, 24: 1378-1386. 10.1128/MCB.24.3.1378-1386.2004.PubMed CentralView ArticlePubMedGoogle Scholar
- Ballmaier M, Zoli M, Leo G, Agnati L, Spano P: Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal-based model of schizophrenia. Eur J Neurosci. 2002, 15: 1197-1205. 10.1046/j.1460-9568.2002.01952.x.View ArticlePubMedGoogle Scholar
- Matsuzaki H, Minabe Y, Nakamura K, Suzuki K, Iwata Y, Sekine Y, Tsuchiya K, Sugihara G, Suda S, Takei N, Nakahara D, Hashimoto K, Nairn A, Mori N, Sato K: Disruption of reelin signaling attenuates methamphetamine-induced hyperlocomotion. Eur J Neurosci. 2007, 25: 3376-3384. 10.1111/j.1460-9568.2007.05564.x.View ArticlePubMedGoogle Scholar
- Baldo B, Kelley A: Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding. Psychopharmacology (Berl). 2007, 191: 439-459. 10.1007/s00213-007-0741-z.View ArticleGoogle Scholar
- Duvauchelle C, Ikegami A, Asami S, Robens J, Kressin K, Castaneda E: Effects of cocaine context on NAcc dopamine and behavioral activity after repeated intravenous cocaine administration. Brain Res. 2000, 862: 49-58. 10.1016/S0006-8993(00)02091-6.View ArticlePubMedGoogle Scholar
- Gong W, Neill D, Lynn M, Justice JJ: Dopamine D1/D2 agonists injected into nucleus accumbens and ventral pallidum differentially affect locomotor activity depending on site. Neuroscience. 1999, 93: 1349-1358. 10.1016/S0306-4522(99)00235-3.View ArticlePubMedGoogle Scholar
- Hemby S, Jones G, Justice JJ, Neill D: Conditioned locomotor activity but not conditioned place preference following intra-accumbens infusions of cocaine. Psychopharmacology (Berl). 1992, 106: 330-336. 10.1007/BF02245413.View ArticleGoogle Scholar
- Pijnenburg A, Honig W, van der Heyden J, van Rossum J: Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity. Eur J Pharmacol. 1976, 35: 45-58. 10.1016/0014-2999(76)90299-5.View ArticlePubMedGoogle Scholar
- Pijnenburg A, van Rossum J: Letter. Stimulation of locomotor activity following injection of dopamine into the nucleus accumbens. J Pharm Pharmacol. 1973, 25: 1003-1005.View ArticlePubMedGoogle Scholar
- Barr A, MacLaurin S, Semenova S, Fish K, Markou A: Altered performance of reelin-receptor ApoER2 deficient mice on spatial tasks using the Barnes maze. Behav Neurosci. 2007, 121: 1101-1105.View ArticlePubMedGoogle Scholar
- Beffert U, Weeber E, Durudas A, Qiu S, Masiulis I, Sweatt J, Li W, Adelmann G, Frotscher M, Hammer R, Herz J: Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron. 2005, 47: 567-579. 10.1016/j.neuron.2005.07.007.View ArticlePubMedGoogle Scholar
- D’Arcangelo G: Apoer2: a reelin receptor to remember. Neuron. 2005, 47: 471-473. 10.1016/j.neuron.2005.08.001.View ArticlePubMedGoogle Scholar
- Krueger D, Howell J, Hebert B, Olausson P, Taylor J, Nairn A: Assessment of cognitive function in the heterozygous reeler mouse. Psychopharmacology (Berl). 2006, 189: 95-104. 10.1007/s00213-006-0530-0.View ArticleGoogle Scholar
- Larson J, Hoffman J, Guidotti A, Costa E: Olfactory discrimination learning deficit in heterozygous reeler mice. Brain Res. 2003, 971: 40-46. 10.1016/S0006-8993(03)02353-9.View ArticlePubMedGoogle Scholar
- Qiu S, Zhao L, Korwek K, Weeber E: Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. J Neurosci. 2006, 26: 12943-12955. 10.1523/JNEUROSCI.2561-06.2006.View ArticlePubMedGoogle Scholar
- Tueting P, Costa E, Dwivedi Y, Guidotti A, Impagnatiello F, Manev R, Pesold C: The phenotypic characteristics of heterozygous reeler mouse. Neuro Report. 1999, 10: 1329-1334.Google Scholar
- Weeber E, Beffert U, Jones C, Christian J, Forster E, Sweatt J, Herz J: Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem. 2002, 277: 39944-39952. 10.1074/jbc.M205147200.View ArticlePubMedGoogle Scholar
- Qiu S, Korwek K, Weeber E: A fresh look at an ancient receptor family: emerging roles for low density lipoprotein receptors in synaptic plasticity and memory formation. Neurobiol Learn Mem. 2006, 85: 16-29. 10.1016/j.nlm.2005.08.009.View ArticlePubMedGoogle Scholar
- Fatemi S: Reelin mutations in mouse and man: from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly. Mol Psychiatry. 2001, 6: 129-133. 10.1038/sj.mp.4000129.View ArticlePubMedGoogle Scholar
- Fatemi S, Earle J, McMenomy T: Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry. 2000, 5: 654-663. 10.1038/sj.mp.4000783. 571View ArticlePubMedGoogle Scholar
- Fatemi S, Hossein Fatemi S, Stary J, Earle J, Araghi-Niknam M, Eagan E: GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr Res. 2005, 72: 109-10.1016/j.schres.2004.02.017.View ArticlePubMedGoogle Scholar
- Fatemi S, Snow A, Stary J, Araghi-Niknam M, Reutiman T, Lee S, Brooks A, Pearce D: Reelin signaling is impaired in autism. Biol Psychiatry. 2005, 57: 777-787. 10.1016/j.biopsych.2004.12.018.View ArticlePubMedGoogle Scholar
- Fatemi S, Stary J, Egan E: Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell Mol Neurobiol. 2002, 22: 139-152. 10.1023/A:1019857620251.View ArticlePubMedGoogle Scholar
- Guidotti A, Auta J, Davis J, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson D, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E: Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000, 57: 1061-1069. 10.1001/archpsyc.57.11.1061.View ArticlePubMedGoogle Scholar
- Impagnatiello F, Guidotti A, Pesold C, Dwivedi Y, Caruncho H, Pisu M, Uzunov D, Smalheiser N, Davis J, Pandey G, Pappas G, Tueting P, Sharma R, Costa E: A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA. 1998, 95: 15718-15723. 10.1073/pnas.95.26.15718.PubMed CentralView ArticlePubMedGoogle Scholar
- Persico A, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, Wassink T, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo M, Pascucci T, Puglisi-Allegra S, Reichelt K, Conciatori M, Marino R, Quattrocchi C, Baldi A, Zelante L, Gasparini P, Keller F: Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry. 2001, 6: 150-159. 10.1038/sj.mp.4000850.View ArticlePubMedGoogle Scholar
- Suzuki K, Nakamura K, Iwata Y, Sekine Y, Kawai M, Sugihara G, Tsuchiya K, Suda S, Matsuzaki H, Takei N, Hashimoto K, Mori N: Decreased expression of reelin receptor VLDLR in peripheral lymphocytes of drug-naive schizophrenic patients. Schizophr Res. 2008, 98: 148-156.View ArticlePubMedGoogle Scholar
- Torrey E, Barci B, Webster M, Bartko J, Meador-Woodruff J, Knable M: Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains. Biol Psychiatry. 2005, 57: 252-260. 10.1016/j.biopsych.2004.10.019.View ArticlePubMedGoogle Scholar
- Podhorna J, Didriksen M: The heterozygous reeler mouse: behavioural phenotype. Behav Brain Res. 2004, 153: 43-54. 10.1016/j.bbr.2003.10.033.View ArticlePubMedGoogle Scholar
- Salinger W, Ladrow P, Wheeler C: Behavioral phenotype of the reeler mutant mouse: effects of RELN gene dosage and social isolation. Behav Neurosci. 2003, 117: 1257-1275.View ArticlePubMedGoogle Scholar
- Qiu S, Korwek K, Pratt-Davis A, Peters M, Bergman M, Weeber E: Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice. Neurobiol Learn Mem. 2006, 85: 228-242. 10.1016/j.nlm.2005.11.001.View ArticlePubMedGoogle Scholar
- Fatemi S, Reutiman T, Folsom T: Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats. Schizophr Res. 2009, 111: 138-152. 10.1016/j.schres.2009.03.002.View ArticlePubMedGoogle Scholar
- Masuzaki H, Jingami H, Matsuoka N, Nakagawa O, Ogawa Y, Mizuno M, Yoshimasa Y, Yamamoto T, Nakao K: Regulation of very-low-density lipoprotein receptor in hypertrophic rat heart. Circ Res. 1996, 78: 8-14. 10.1161/01.RES.78.1.8.View ArticlePubMedGoogle Scholar
- Jokinen E, Landschulz K, Wyne K, Ho Y, Frykman P, Hobbs H: Regulation of the very low density lipoprotein receptor by thyroid hormone in rat skeletal muscle. J Biol Chem. 1994, 269: 26411-26418.PubMedGoogle Scholar
- Howell BW, Herrick TM, Hildebrand JD, Zhang Y, Cooper JA: Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Curr Biol. 2000, 10: 877-885. 10.1016/S0960-9822(00)00608-4.View ArticlePubMedGoogle Scholar
- Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer R, Richardson J, Herz J: Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell. 1999, 97: 689-701. 10.1016/S0092-8674(00)80782-5.View ArticlePubMedGoogle Scholar
- Sato Y, Taoka M, Sugiyama N, Kubo K, Fuchigami T, Asada A, Saito T, Nakajima K, Isobe T, Hisanaga S: Regulation of the interaction of Disabled-1 with CIN85 by phosphorylation with Cyclin-dependent kinase 5. Genes Cells. 2007, 12: 1315-1327. 10.1111/j.1365-2443.2007.01139.x.View ArticlePubMedGoogle Scholar
- Shimokawa N, Haglund K, Hölter S, Grabbe C, Kirkin V, Koibuchi N, Schultz C, Rozman J, Hoeller D, Qiu C, Londoño M, Ikezawa J, Jedlicka P, Stein B, Schwarzacher S, Wolfer DP, Ehrhardt N, Heuchel R, Nezis I, Brech A, Schmidt M, Fuchs H, Gailus-Durner V, Klingenspor M, Bogler O, Wurst W, Deller T, de Angelis M, Dikic I: CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice. EMBO J. 2010, 29: 2421-2432. 10.1038/emboj.2010.120.PubMed CentralView ArticlePubMedGoogle Scholar
- Amaral D, Schumann C, Nordahl C: Neuroanatomy of autism. Trends Neurosci. 2008, 31: 137-145. 10.1016/j.tins.2007.12.005.View ArticlePubMedGoogle Scholar
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. 1994, American Psychiatric Association, Washington, DC, 4Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.