The involvement of Reelin in neurodevelopmental disorders

Abstract

Reelin is a glycoprotein that serves important roles both during development (regulation of neuronal migration and brain lamination) and in adults (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 is currently unknown although possible explanations include early developmental insults, mutations, hypermethylation of the promoter for the Reelin gene (RELN), miRNA silencing of Reelin mRNA, and Reelin processing abnormalities. Increasing Reelin expression through pharmacological therapies may help ameliorate symptoms resulting from Reelin deficits.

A comparison of a single genetic factor, two stress factors, and one psychosocial coping factor as predictors of depression in an Australian community sample.

“…It may be that further exploration of the influence of psychological resilience in those participants might clarify the ways in which the gene x environment interaction occurs. Although resilience appears to have genetic indicators [24,58], no study to date has used that data to investigate how resilience might interact with 5-HTTLPR and stress to influence depressive status, and that is a potential fruitful avenue of future research into ways of identifying those people who are most at-risk of developing depression following either recent or past stressors, and for identifying them in everyday clinical practice settings. As well as being of potential value to patients with MDD themselves, resilience may also be a factor in the wellbeing of the families of those patients, who suffer from considerable burden themselves [59].…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…RELN is expressed in Cajal-Retzius cells during early development and from many GABAergic cells in multiple cortical layers shortly after birth (Alcantara et al, 2006). Brain tissue from schizophrenic patients also consistently report decreased expression of the RELN gene Fatemi et al, 2000Fatemi et al, , 2001Folsom and Fatemi, 2013;Guidotti et al, 2000a;Habl et al, 2012;Impagnatiello et al, 1998;Maloku et al, 2010;Ruzicka et al, 2007), which is likely the result of altered genetic and/ or epigenetic regulation (Costa et al, 2003;Grayson et al, 2005Grayson et al, , 2006Tochigi et al, 2008;Veldic et al, 2004Veldic et al, , 2007. While the RELN deficiency observed in post-mortem tissue clearly does not impact cortical architecture to the same degree as total RELN loss during cortical development, it is likely that even a small reduction of RELN would affect synaptic integration during development and/or synaptic stability and plasticity in adulthood (Frotscher, 2010).…”

Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex

“…Seven genes, Gria1, Gria2, Grm3, Gabra1, Abat, Dlg4 and Ntrk12, showed upregulated mRNA levels, whereas only 1 gene, Reln, showed significantly down regulated mRNA. Reelin level variations are highly relevant in psychotic disorders, 32 hence we also investigated Reelin protein expression upon THC exposure. We found decreased levels of Reelin isoforms 410 KDa and 180 KDa, whereas Reelin 330 KDa was unchanged (Appendix 1, Fig.…”