Reelin Alterations, Behavioral Phenotypes, and Brain Anomalies in Schizophrenia: A Systematic Review of Insights From Rodent Models

Abstract

Reelin is an extracellular matrix glycoprotein reduced in brain regions (the prefrontal cortex and the hippocampus) of patients with schizophrenia. There are diverse rodent models of schizophrenia that mimic patient symptoms based on various causal theories; however, likely shared reelin alterations have not yet been systematically assessed in those models. A systematic review of the literature was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model. Articles focused on psychotic disorders or schizophrenia and their relationship with reelin in rodent models were selected. Data (first author, publication year, results, both open field and prepulse inhibition test results, and type of reelin alteration) were extracted in duplicate by two independent reviewers. The 37 reviewed articles reported about various schizophrenia models and their reelin alterations, brain morphology, and behavioral defects. We conclude that reelin is an altered preclinical biomarker common to all models included, mainly prenatal or genetic models, and a key protein in schizophrenia disease, making the reelin signaling pathway in prenatal stages a target of special interest for future preclinical and clinical studies. All models presented at least one of the four described reelin alteration types.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021210568], identifier [CRD42021210568].

HeterozygousDab1Null Mutation Disrupts Neocortical and Hippocampal Development

“…Similar to the Dab1 gene, the Reelin gene is also known to exhibit haploinsufficiency (Liu et al, 2001;Carboni et al, 2004;Qiu et al, 2006;Nullmeier et al, 2011;Bouamrane et al, 2016;Wang et al, 2019), and reduced Reelin levels have been observed in the brains of patients with schizophrenia (Impagnatiello et al, 1998;Guidotti et al, 2000), bipolar disorder (Guidotti et al, 2000), autism (Fatemi et al, 2001;Fatemi et al, 2005), and Alzheimer's disease (Chin et al, 2007). Moreover, heterozygous reeler mice and Reelin ΔC-KI mice exhibit similar neurochemical, behavioral, and cognitive abnormalities to those observed in autism or schizophrenia (Costa et al, 2001;Tremolizzo et al, 2002;Carboni et al, 2004;Nullmeier et al, 2011;Sakai et al, 2016;Sanchez-Hidalgo et al, 2022). The anatomical abnormalities we observed in heterozygous yotari mice may also be related to behavioral defects because layer 1 and hippocampus are essential for higher-order cognitive functions (Hainmueller and Bartos, 2020;Schuman et al, 2021).…”

Reelin Plasma Levels Identify Cognitive Decline in Alcohol Use Disorder Patients During Early Abstinence: The Influence of APOE4 Expression

“…In this study, higher plasma levels of reelin were observed in patients with AUD compared with controls. Altered reelin levels in the brain, CSF, or plasma have been reported in animal models and humans with several neuropsychiatric disorders ( Ishii et al, 2016 ; Sánchez-Hidalgo et al, 2022 ). However, most studies are genetic or focused on brain reelin levels, and the exact contribution of peripheral reelin to cognition is largely unknown.…”

Distinctive Patterns of 5-Methylcytosine and 5-Hydroxymethylcytosine in Schizophrenia

“…In humans, the dysregulation of Reelin protein is associated with various neurological disorders, including schizophrenia, BD, autism, depression, and more [ 39 , 40 ]. Reelin was found to be altered in various animal models of schizophrenia, suggesting its key role in the pathogenesis of schizophrenia [ 41 ]. Reelin levels were significantly reduced in schizophrenia patients, with specific gender differences [ 42 ].…”