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.