Invited reviewThe involvement of Reelin in 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.
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2022, Behavioural Brain ResearchCitation 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].
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