Reelin and Neuropsychiatric Disorders

Abstract

Proper neuronal migration and laminar formation during corticogenesis is essential for normal brain function. Disruption of these developmental processes is thought to be involved in the pathogenesis of some neuropsychiatric conditions. Especially, Reelin, a glycoprotein mainly secreted by the Cajal-Retzius cells and a subpopulation of GABAergic interneurons, has been shown to play a critical role, both during embryonic and postnatal periods. Indeed, animal studies have clearly revealed that Reelin is an essential molecule for proper migration of cortical neurons and finally regulates the cell positioning in the cortex during embryonic and early postnatal stages; by contrast, Reelin signaling is closely involved in synaptic function in adulthood. In humans, genetic studies have shown that the reelin gene (RELN) is associated with a number of psychiatric diseases, including Schizophrenia (SZ), bipolar disorder (BP) and autistic spectrum disorder. Indeed, Reln haploinsufficiency has been shown to cause cognitive impairment in rodents, suggesting the expression level of the Reelin protein is closely related to the higher brain functions. However, the molecular abnormalities in the Reelin pathway involved in the pathogenesis of psychiatric disorders are not yet fully understood. In this article, we review the current progress in the understanding of the Reelin functions that could be related to the pathogenesis of psychiatric disorders. Furthermore, we discuss the basis for selecting Reelin and molecules in its downstream signaling pathway as potential therapeutic targets for psychiatric illnesses.

Disrupted in Schizophrenia 1 regulates the processing of reelin in the perinatal cortex

“…Shortly after its identification, reduced levels of reelin were noted in schizophrenia patients , with specific species of the reelin protein later shown to be deregulated in this condition, bipolar disorder and depression (Fatemi et al, 2001). Similar results have also been reported since by others, while a considerable number of genetic association studies also associated it with schizophrenia and autism spectrum disorders (reviewed in Ishii et al, 2016). Negative genetic association findings to mental illness have also been reported, although one positive finding was at the genome-wide level (Shifman et al, 2008).…”

Evaluation of RELN gene polymorphism in children with autism spectrum disorder

“…25,26 Önceki çalışmalar, reelinin N-metil-d-aspartat (NMDA) reseptör sinyali de dahil olmak üzere, sinaptik işlevlerin düzenlen-mesinde önemli bir role sahip olduğunu göster-miştir. 27 Prefrontal kortekste glutamergik transmisyonun, prefrontal korteks işlevlerinin belirlenmesinde önemli bir rolünün olduğu belirtilmiştir. 28 Çalışmalarda NMDA reseptör bozukluklarının DEHB ve otizm gibi nörogelişimsel bozukluklarla ilişkili olduğu gösterilmiştir.…”

Increased densities of white matter neurons as a cross‐disease feature of neuropsychiatric disorders

“…Other risk genes for neuropsychiatric disorders have also been shown to be involved in neuronal migration during development, and animal studies indicate the existence of an association between abnormal neuronal migration and brain dysfunction. Reelin plays important roles in both neuronal migration and cortical layering of the cerebral cortex and cerebellum . Genetic mutations that lead to functional weakness of Reelin have been shown to cause slight cortical abnormalities, including the increase in the number of neurons in the WM and abnormal brain function, in mutant mice during their adulthood .…”

“…Reelin plays important roles in both neuronal migration and cortical layering of the cerebral cortex and cerebellum. [54][55][56][57] Genetic mutations that lead to functional weakness of Reelin have been shown to cause slight cortical abnormalities, including the increase in the number of neurons in the WM and abnormal brain function, in mutant mice during their adulthood. 58,59 Contactin-associated protein-like 2 (Cntnap2) encodes a neuronal transmembrane protein, a member of the neurexin superfamily, and has been shown to be associated with the risk of development of various neuropsychiatric disorders, including ASD, intellectual disability, attention deficit hyperactivity disorder, epilepsy, and schizophrenia.…”