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Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology - PubMed

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Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology

C A Tamminga et al. Neuroscience. 2015.

Abstract

The hippocampus is strongly implicated in the psychotic symptoms of schizophrenia. Functionally, basal hippocampal activity (perfusion) is elevated in schizophrenic psychosis, as measured with positron emission tomography (PET) and with magnetic resonance (MR) perfusion techniques, while hippocampal activation to memory tasks is reduced. Subfield-specific hippocampal molecular pathology exists in human psychosis tissue which could underlie this neuronal hyperactivity, including increased GluN2B-containing NMDA receptors in hippocampal CA3, along with increased postsynaptic density protein-95 (PSD-95) along with augmented dendritic spines on the pyramidal neuron apical dendrites. We interpret these observations to implicate a reduction in the influence of a ubiquitous gene repressor, repressor element-1 silencing transcription factor (REST) in psychosis; REST is involved in the age-related maturation of the NMDA receptor from GluN2B- to GluN2A-containing NMDA receptors through epigenetic remodeling. These CA3 changes in psychosis leave the hippocampus liable to pathological increases in neuronal activity, feedforward excitation and false memory formation, sometimes with psychotic content.

Keywords: CA3; REST; polychrome proteins; schizophrenia; synaptic plasticity.

Copyright © 2015. Published by Elsevier Ltd.

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Figures

Figure 1
Figure 1. Model showing REST-dependent epigenetic remodeling of the grin2b promoter

REST binds to the RE1 element within the promoter of its target gene grin2b and recruits mSin3A and CoREST, HDACs-1/2, G9a and MeCP2. The REST-corepressor complex promotes epigenetic remodeling of core histone proteins at the grin2b promoter. Recruitment of EZH2 in the promoter of grin2b confers trimethylation on lysine 27 of core histone protein H3. These may play a crucial role in acquisition of the mature NMDAR phenotype during postnatal development. Modified with permission from Noh et al, Proc Natl Acad Sci USA 109:E962-7.

Figure 2
Figure 2. The Polycomb group protein EZH2 confers epigenetic marks of gene repression

The Polycomb group protein EZH2 acts as part of the Polycomb Repressive Complexes 2 and 3 (PRC2/3), which add methyl groups to histone proteins. EZH2 is recruited to the promoter region of target genes. such as grin2b, where it confers three methyl marks to lysine 27 in histone 3. This mark is possibly the most enduring mark of gene represson. EZH2 may also have a role in recruiting other repressive proteins such as DNMT1methyl-binding domain protein. Adapted from Viré et al, Nature 439:794–795.

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