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 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'.

Figure 1

The Reelin signaling system. Extracellular Reelin glycoprotein binds to its receptors APOER2, VLDLR, and α3β1 integrin directly, initiating the signaling system in the effector cells. Reelin induction of the cascade leads to clustering of the receptors and ephrin B proteins causing clustering of DAB1 proteins and activation of Src-tyrosine kinase family/Fyn-kinase which phosphorylates DAB1 on four tyrosine residues. This leads to the recruitment and activation of kinase cascade including PI3K, PKB/AKT1 leading to inhibition of GSK3β. GSK3β normally phosphorylates tau, which promotes microtubule stability. DAB1 activation also leads to the recruitment of LIS1 which also affects microtubule dynamics. These processes promote neuronal migration and brain lamination. APOER2, PI3K, and DAB1 contribute to phosphorylation of cofilin which in turn stabilizes the actin cytoskeleton preventing cell migration, suggesting that Reelin may act as a stop signal. Finally, Reelin has a direct effect on enhancement of long term potentiation (LTP), via direct involvement of its receptors VLDLR and ApoER2. APOER2, associates with scaffolding protein PSD95, which helps couple the Reelin signaling complex with the NMDA receptor (NMDAR). Tyrosine phosphorylation of NMDAR subunits NR2A and NR2B by Fyn kinase results in Ca²⁺ influx through NMDAR, and ultimately induction of LTP and modulation of synaptic plasticity; potentially converging on Reelin’s role in cognition and memory processing. Reprinted in a modified form by permission from Nature Publishing Group, a division of MacMillan Publishers, LTD.: Fatemi, S.H. Molecular Psychiatry 10, 251–257, copyright 2005.

Figure 2

Multiple mechanisms to account for altered Reelin expression in neuropsychiatric disorders. Please see section 9 for further discussion.