Reelin-related neurological disorders and animal models

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Background

The Reeler mutation, first described by Falconer in 1951, was so named according to the typical alterations in gait that characterize the recessive homozygous (Hom) mice. Several decades after the description of the Reeler phenotype, the mutated protein was discovered and named Reelin (Reln). Reln controls a number of fundamental phases during embryonic and postnatal brain development. As a consequence, Hom mutants show disrupted cell layering in the cerebral cortex and hippocampus, and a very small non-foliated cerebellum. Heterozygous mutants (Het) exhibit defects in dendrite extension and synapse formation, correlating with behavioral and cognitive deficits that are detectable at adult ages. Reln is expressed mainly by Cajal-Retzius cells in the marginal zone embryonic forebrain, where it directs the radial migration of principal neurons. The expression pattern of Reln changes once neurogenesis is completed, and - in the adult brain - Reln is mainly produced by a subset of GABAergic interneurons throughout the neocortex and hippocampus.

The gene encoding for the protein is highly conserved between the mouse (Reln) and the human (RELN). In humans, RELN is correlated with psychiatric and cognitive disorders, as originally demonstrated by a significant 50% reduction of RELN mRNA and protein in cerebellar, hippocampal and frontal cortices of patients with schizophrenia (SZ), and similar reductions in RELN have also been observed in autistic individuals. Following these initial observations RELN has been implicated in the aetiology of at least six human neurological disorders: Alzheimer disease (AD), SZ, autism spectrum disorder (ASD), bipolar disorder, major depression, and lissencephaly with cerebellar hypoplasia. More specifically, a total RELN deficiency in humans is causative of one of the several forms of lissencephalies that are related to neuronal migration disorders, and the behavioural/brain structural phenotype (but not the genotype) of SZ and ASD patients is reminiscent of that of the Reeler Het mouse.

Despite the wealth of structural and functional investigations on the Reeler brain and the dissection of the Reln signaling system, much remains to be done to fully understand the consequences of Reln deficiency on the development and function of the human brain. Using state-of-the-art genetic approaches and engineered mutant mice new information has been obtained in recent year that will facilitate mouse-human comparison.

At the junction between normal and pathological development, this Research Topic aims to provide multilayered genotype-to-phenotype correlation, and to critically assess the current literature on molecular mechanisms associated with Reln signaling in mice used to model human psychiatric and neurodegenerative conditions. The studies will include experimental strategies that range from behavioral to structural and functional characterization, with cell (receptors and intracellular pathways, mechanisms of cell death) and network analysis (neurochemistry; morphology, numbers and distribution of excitatory and inhibitory neurons; principles of axonal connections), pharmacological characterization and neuroimaging. Primary attention will be paid to the links of Reln genetic background with age, sex, strain, and relation with the immune system during pre- and postnatal life.

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