Elsevier

Neuropharmacology

Volume 68, May 2013, Pages 122-135
Neuropharmacology

Invited review
The involvement of Reelin in neurodevelopmental disorders

https://doi.org/10.1016/j.neuropharm.2012.08.015Get rights and content

Abstract

Reelin is a glycoprotein that serves important roles both during development (regulation of neuronal migration and brain lamination) and in adulthood (maintenance of synaptic function). A number of neuropsychiatric disorders including autism, schizophrenia, bipolar disorder, major depression, Alzheimer's disease and lissencephaly share a common feature of abnormal Reelin expression in the brain. Altered Reelin expression has been hypothesized to impair neuronal connectivity and synaptic plasticity, leading ultimately to the cognitive deficits present in these disorders. The mechanisms for abnormal Reelin expression in some of these disorders are currently unknown although possible explanations include early developmental insults, mutations, hypermethylation of the promoter for the Reelin gene (RELN), miRNA silencing of Reelin mRNA, FMRP underexpression and Reelin processing abnormalities. Increasing Reelin expression through pharmacological therapies may help ameliorate symptoms resulting from Reelin deficits.

This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.

Highlights

► Reelin plays important roles in neuronal migration and brain development. ► Reelin is an important modulator of synaptic function. ► Reelin expression is altered in disorders such as schizophrenia and autism. ► Reelin is an important potential therapeutic target.

Section snippets

Chemistry of Reelin

Reelin glycoprotein plays a number of important roles in the central nervous system (CNS) developmentally including mediating neuronal cell migration and proper brain lamination, while in the mature brain it is involved in modulating synaptic function. The gene for Reelin (RELN) in humans is located on chromosome seven (DeSilva et al., 1997) and its protein product is a secreted extracellular matrix protein (DeBergeyck et al., 1998). On SDS-PAGE, Reelin appears as multiple protein bands: Reelin

Genetics

The gene for Reelin (RELN) is located at 7q22.1 in humans (D'Arcangelo et al., 1995; DeSilva et al., 1997) and at chromosome 5 in mice (D'Arcangelo et al., 1995). The mouse RELN gene was found to contain 65 exons, spanning 450 kb of DNA (Royaux et al., 1997). Consequences of RELN mutation were first characterized in the homozygous reeler mouse which phenotypically exhibited an ataxic gait (Curran and D'Arcangelo, 1998; Falconer, 1951; Tissir and Goffinet, 2003). A number of abnormalities have

Reelin receptors

Reelin binds two main receptors: apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR) (D'Arcangelo et al., 1999; Hiesberger et al., 1999). Recent work has elucidated the important roles of these receptors in mediating cell migration and the establishment of proper cytoarchitecture of the brain. Evidence from Vldlr and Apoer2 knockout mice suggest that the receptors may have divergent roles in neuronal migration with APOER2 being required to enable migration

Reelin signaling

The Reelin signaling pathway has been characterized through the work of multiple laboratories (Herz and Chen, 2006; Jossin, 2011). Extracellular Reelin glycoprotein is secreted by Cajal–Retzius cells; certain cortical and hippocampal gamma-aminobutyric acid (GABA)ergic cells; and cerebellar granule cells (Del Río et al., 1997; Curran and D'Arcangelo, 1998; Frotscher, 1998). Reelin has also been identified as present in glial somata and astrocytic processes at much lower levels than in neurons (

Reelin and cognition

During development, there is a shift in Reelin expression from Cajal–Retzius cells to GABAergic interneurons in the neocortex and hippocampus. Additionally, Reelin is expressed by granule cells in the cerebellum, pyramidal cells in the entorhinal cortex in adults, and glial cells (Abraham and Meyer, 2003; Alcántara et al., 1998; Chin et al., 2007; Doehner and Knuesel, 2010; Lacor et al., 2000; Miettinen et al., 2005; Pesold et al., 1998; Roberts et al., 2005). Recent evidence has shown that the

The role of Reelin in schizophrenia

Multiple biological theories have been proposed to explain the origins of schizophrenia including neurodegenerative changes or disruptions of the dopaminergic, serotonergic, or glutamatergic signaling systems (Fatemi, 2008). Social factors including migration and urban birth and upbringing have also been implicated in etiology of schizophrenia (Kneeland and Fatemi, 2012). Additionally, abuse of drugs such as cannabis, amphetamines or LSD can produce psychotic symptoms and may lead to the

Reelin and autism

Autism is a debilitating neurodevelopmental disorder characterized by deficits in cognition, communication, and social interaction. Brains from subjects with autism display multiple pathologies including brain volume abnormalities including macrocephaly, minicolumnar structural abnormalities in the neocortex, and white and gray matter abnormalities (Bailey et al., 1993; Bauman and Kemper, 2005; Casanova et al., 2002; Courchesne et al., 2003; Fatemi et al., 2012; Palmen et al., 2004; Schumann

Reelin in other neuropsychiatric disorders

Altered expression of Reelin has been associated with additional brain disorders including Alzheimer's disease (AD), lissencephaly, bipolar disorder, and major depression. Alzheimer's disease (AD) is the most common form of senile dementia. It is characterized by progressive cognitive impairment. In brain, AD is characterized with the presence of extracellular deposits consisting mainly of beta amyloid (Aβ) peptides and intracellular neurofibrillary tangles consisting mainly of phosphorylated

Potential mechanisms for reduced Reelin expression in neuropsychiatric disorders

Reduced Reelin expression may be the result of multiple mechanisms. Spontaneous mutations of the RELN gene itself could result in reduced or absent Reelin expression as shown with the homozygous reeler mouse. As mentioned in the previous section, a mutation in RELN leads to LIS-CH and an absence of serum Reelin (Hong et al., 2000; Chang et al., 2007).

Reelin haploinsufficiency may be a second potential mechanism to cause altered Reelin expression (Fig. 2). As discussed in Section 5, the HRM has

Potential involvement of Reelin in pharmacotherapeutics

Therapies that increase Reelin expression may ameliorate some of the symptoms of these disorders. As mentioned in Section 5, Reelin supplementation to cultured neurons has been shown to enhance LTP. In a recent study, injection of purified Reelin into the ventricles of wild-type mice has been shown to result in increased hippocampal CA1 LTP, and improved performance on tasks measuring associative and spatial learning and memory (Rogers et al., 2011).

Chronic treatment with a typical

Conclusions

Reelin protein is required for proper brain development and synaptic plasticity. Disrupted Reelin expression has been identified in a number of neurodevelopmental disorders including autism, schizophrenia, as well as other neuropsychiatric disorders such as lissencephaly, Alzheimer's disease, bipolar disorder, and major depression. The clinical phenotypes of these diverse conditions may be partially the result of improper neuronal migration, aberrant brain cytoarchitecture, and impaired synapse

Acknowledgments

Grant support by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD052074-01A2) and the National Institute of Mental Health (5R01MH086000-01A2) and the Minnesota Medical Foundation Alfred and Ingrid Lenz Harrison Initiative Fund to SHF is gratefully acknowledged. Dr. Fatemi has several United States patents (7341844) on the use of Reelin as a diagnostic marker in psychiatric disorders but has not derived any financial gains from these patents.

References (219)

  • G. D'Arcangelo et al.

    Reelin is a ligand for lipoprotein receptors

    Neuron

    (1999)
  • J.C. Darnell et al.

    FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism

    Cell

    (2011)
  • V. DeBergeyck et al.

    A panel of monoclonal antibodies against reelin, the extracellular matrix protein defective in reeler mutant mice

    J. Neurosci. Meth.

    (1998)
  • S. De Rubeis et al.

    Fragile X mental retardation protein control of neuronal mRNA metabolism: insights into mRNA stability

    Mol. Cell. Neurosci.

    (2010)
  • L. Dulabon et al.

    Reelin binds alpha 3 beta 1 integrin and inhibits neuronal migration

    Neuron

    (2000)
  • S. Dutta et al.

    Genetic analysis of reelin gene (RELN) SNPs: no association with autism spectrum disorder in the Indian population

    Neurosci. Lett.

    (2008)
  • S.H. Fatemi et al.

    Reelin signaling is impaired in autism

    Biol. Psychiatry

    (2005)
  • S.H. Fatemi et al.

    Chronic psychotropic drug treatment causes differential expression of reelin signaling system in frontal cortex of rats

    Schizophr. Res.

    (2009)
  • S.H. Fatemi et al.

    Fragile X mental retardation protein levels are decreased in major psychiatric disorders

    Schizophr. Res.

    (2010)
  • M. Frotscher

    Cajal–Retzius cells, reelin, and the formation of layers

    Curr. Opin. Neurobiol.

    (1998)
  • M.M. Ghahramani Seno et al.

    Gene and miRNA expression profiles in autism spectrum disorders

    Brain Res.

    (2011)
  • D. Goldowitz et al.

    Performance of normal and neurological mutant mice on radial arm maze and active avoidance tasks

    Behav. Neural Biol.

    (1986)
  • L. Greenbaum et al.

    Association of reelin (RELN) single nucleotide polymorphism rs7341475 with prepulse inhibition in the Jewish Israeli population

    Biol. Psychiatry

    (2011)
  • A. Guidotti et al.

    Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling

    Trends Pharmacol. Sci.

    (2009)
  • A. Guidotti et al.

    Epigenetic GABAergic targets in schizophrenia and bipolar disorder

    Neuropharmacology

    (2011)
  • H.M. Abdolmaleky et al.

    Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report

    Am. J. Med. Genet. B Neuropsychiatr. Genet.

    (2005)
  • H. Abraham et al.

    Reelin-expressing neurons in the postnatal and adult human hippocampal formation

    Hippocampus

    (2003)
  • S. Akbarian et al.

    Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development

    Arch. Gen. Psychiatry

    (1993)
  • S. Alcántara et al.

    Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse

    J. Neurosci.

    (1998)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • M. Ammassari-Teule et al.

    Reelin haploinsufficiency reduces the density of PV+ neurons in circumscribed regions of the striatum and selectively alters striatal-based behaviors

    Psychopharmacology (Berl.)

    (2009)
  • D. Antoniades et al.

    The role of reelin gene polymorphisms in the pathogenesis of Alzheimer's disease in a Greek population

    J. Biol. Regul. Homeost. Agents

    (2011)
  • S.E. Arnold et al.

    Recent advances in defining the neuropathology of schizophrenia

    Acta Neuropath.

    (1997)
  • L. Arseneault et al.

    Causal association between cannabis and psychosis: examination of the evidence

    Br. J. Psychiatry

    (2004)
  • A.E. Ashley-Koch et al.

    Investigation of potential gene–gene interactions between APOE and RELN contributing to autism risk

    Psychiatr. Genet.

    (2007)
  • A.H. Assadi et al.

    Interaction of reelin signaling and Lis1 in brain development

    Nat. Genet.

    (2003)
  • E. Barkus et al.

    The presence of neurological soft signs along the psychosis proneness continuum

    Schizophr. Bull.

    (2006)
  • A.M. Barr et al.

    Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins

    Eur. J. Neurosci.

    (2008)
  • M.L. Bauman et al.

    Structural brain anatomy in autism: what is the evidence?

  • E. Ben-David et al.

    Further investigation of the association between rs7341475 and rs17746501 and schizophrenia

    Am. J. Med. Genet. B Neuropsychiatr. Genet.

    (2010)
  • E. Bonora et al.

    Analysis of reelin as a candidate gene for autism

    Mol. Psychiatry

    (2003)
  • A. Botella-López et al.

    Reelin expression and glycosylation patterns are altered in Alzheimer's disease

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • M.P. Boyle et al.

    Cell-type-specific consequences of reelin deficiency in the mouse neocortex, hippocampus, and amygdala

    J. Comp. Neurol.

    (2011)
  • J.L. Brigman et al.

    Executive functions in the heterozygous reeler mouse model of schizophrenia

    Behav. Neurosci.

    (2006)
  • A.S. Brown

    Prenatal infection as a risk factor for schizophrenia

    Schizophr. Bull.

    (2006)
  • M.F. Casanova et al.

    Minicolumnar pathology in autism

    Neurology

    (2002)
  • X. Chai et al.

    Reelin acts as a stop signal for radially migrating neurons by inducing phosphorylation of n-cofilin at the leading edge

    Commun. Integr. Biol.

    (2009)
  • B.S. Chang et al.

    The role of RELN in lissencephaly and neuropsychiatric disease

    Am. J. Med. Genet. B Neuropsychiatr. Genet.

    (2007)
  • L.H. Chang et al.

    Association of RELN promoter SNPs with schizophrenia in the Chinese population

    Dongwuxue Yanjiu

    (2011)
  • Y. Chen et al.

    Reelin modulates NMDA receptor activity in cortical neurons

    J. Neurosci.

    (2005)
  • Cited by (211)

    • Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks

      2022, Behavioural Brain Research
      Citation Excerpt :

      This signaling pathway results in increased long-term potentiation of synapses, which was proposed to correlate with learning and memory [10,11]. Clinical genetic studies revealed that RELN is associated with several neuropsychiatric disorders, including schizophrenia and autism spectrum disorder [12,13]. Of note, several rare variants of RELN have been identified as risk factors for schizophrenia such as de novo or rare missense variants and exonic deletion of RELN [14–16].

    View all citing articles on Scopus
    View full text