Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders
REELN (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, RELN binds to VLDL, APOE2, and 32 Integrin receptors located on dendritic shafts and spines of postsynaptic pyramidal...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-04-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncel.2016.00089/full |
| _version_ | 1828843263811911680 |
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| author | Alessandro eGuidotti Dennis R Grayson Hector M Caruncho |
| author_facet | Alessandro eGuidotti Dennis R Grayson Hector M Caruncho |
| author_sort | Alessandro eGuidotti |
| collection | DOAJ |
| description | REELN (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, RELN binds to VLDL, APOE2, and 32 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 RELNn 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. 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. |
| first_indexed | 2024-12-12T20:42:25Z |
| format | Article |
| id | doaj.art-aae5dcc5e2aa4f81ad50be7b75ffee70 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-12T20:42:25Z |
| publishDate | 2016-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-aae5dcc5e2aa4f81ad50be7b75ffee702022-12-22T00:12:41ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022016-04-011010.3389/fncel.2016.00089186928Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric DisordersAlessandro eGuidotti0Dennis R Grayson1Hector M Caruncho2The Psychiatric InstituteThe Psychiatric InstituteUniversity of SaskatchewanREELN (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, RELN binds to VLDL, APOE2, and 32 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 RELNn 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. 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.http://journal.frontiersin.org/Journal/10.3389/fncel.2016.00089/fullBipolar DisorderSchizophreniasynaptic plasticityreelinpromoter methylation |
| spellingShingle | Alessandro eGuidotti Dennis R Grayson Hector M Caruncho Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders Frontiers in Cellular Neuroscience Bipolar Disorder Schizophrenia synaptic plasticity reelin promoter methylation |
| title | Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders |
| title_full | Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders |
| title_fullStr | Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders |
| title_full_unstemmed | Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders |
| title_short | Epigenetic Reelin Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders |
| title_sort | epigenetic reelin dysfunction in schizophrenia and related neuropsychiatric disorders |
| topic | Bipolar Disorder Schizophrenia synaptic plasticity reelin promoter methylation |
| url | http://journal.frontiersin.org/Journal/10.3389/fncel.2016.00089/full |
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