Epigenetic RELN Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders.
journal contributionposted on 2016-06-21, 00:00 authored by A Guidotti, DR Grayson, HJ Caruncho
REELIN (RELN) is a large (420 kDa) glycoprotein that in adulthood is mostly synthesized in GABAergic neurons of corticolimbic structures. Upon secretion in the extracellular matrix (ECM), RELN binds to VLDL, APOE2, and α3β2 Integrin receptors located on dendritic shafts and spines of postsynaptic pyramidal neurons. Reduced levels of RELN expression in the adult brain induce cognitive impairment and dendritic spine density deficits. RELN supplementation recovers these deficits suggesting a trophic action for RELN in synaptic plasticity. We and others have shown that altered RELN expression in schizophrenia (SZ) and bipolar (BP) disorder patients is difficult to reconcile with classical Mendelian genetic disorders and it is instead plausible to associate these disorders with altered epigenetic homeostasis. Support for the contribution of altered epigenetic mechanisms in the down-regulation of RELN expression in corticolimbic structures of psychotic patients includes the concomitant increase of DNA-methyltransferases and the increased levels of the methyl donor S-adenosylmethionine (SAM). It is hypothesized that these conditions lead to RELN promoter hypermethylation and a reduction in RELN protein amounts in psychotic patients. The decreased synthesis and release of RELN from GABAergic corticolimbic neurons could serve as a model to elucidate the epigenetic pathophysiological mechanisms acting at pyramidal neuron dendrites that regulate synaptic plasticity and cognition in psychotic and non-psychotic subjects.
AG is supported by the following NIH grants AA022538, R01 MH093348, R01 MH101043, DRG is supported by AA022538. HJC is supported by a SHRF Establishment Grant, and a NSERC Discovery grant.
Publisher StatementThis Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission. © 2016 Frontiers Media Publications. © 2016, Guidotti, Grayson and Caruncho.