Editing Reelin (section)

=== Schizophrenia ===
Reduced expression of reelin and its [[Messenger RNA|mRNA]] levels in the brains of [[schizophrenia]] sufferers had been reported in 1998<ref name="szproof1" /> and 2000,<ref name="szproof2" /> and independently confirmed in postmortem studies of the hippocampus,<ref name="szconfirm1" /> [[cerebellum]],<ref name="pmid15560956" /> [[basal ganglia]],<ref name="BDP_basal_ganglia_2007" /> and cerebral cortex.<ref name="szconfirm2" /><ref name="szconfirm3" /> The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of [[GAD-67]] [[enzyme]],<ref name="pmid15560956" /> which catalyses the transition of [[glutamate]] to [[GABA]]. [[Blood test|Blood levels]] of reelin and its [[isoform]]s are also altered in schizophrenia, along with [[mood disorder]]s, according to one study.<ref name="fatemi_blood_reelin" /> Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.<ref name="Knable_2001" />

[[Epigenetics|Epigenetic]] hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,<ref name="hypermeth" /><ref name="dong" /> in agreement with the observations dating from the 1960s that administration of [[methionine]] to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients.<ref name="methionine1" /><ref name="methionine2" /><ref name="methionine3" /><ref name="methionine4" /> The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; [[Erminio Costa|E. Costa]]).<ref name="Schizophrenia Research Forum: Current Hypotheses" /><ref name="pmid19395859" /> A postmortem study comparing a [[DNA methyltransferase]] ([[DNA methyltransferase#DNMT 1|DNMT1]]) and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression.<ref name="epigenetic2007" /> There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours.<ref name="DNMT_inhibition_GAD67_Reelin_2004" /><ref name="pmid15684088" /> [[Methylation]] inhibitors and [[histone deacetylase]] inhibitors, such as [[valproic acid]], increase reelin mRNA levels,<ref name="valpro" /><ref name="valproicreelin" /><ref name="Mitchell" /> while L-methionine treatment downregulates the phenotypic expression of reelin.<ref name="l-meth" />

One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients.<ref name="pmid17553960" /> Histone deacetylases suppress gene promoters; hyperacetylation of histones was shown in murine models to demethylate the promoters of both reelin and GAD67.<ref name="Dong_2007" /> DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67,<ref name="DNMT_inhibition_GAD67_Reelin_2006" /> and both DNMT inhibitors and HDAC inhibitors shown in one study<ref name="pmid19029285" /> to activate both genes with comparable dose- and time-dependence. As one study shows, [[S-adenosyl methionine]] (SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people.<ref name="SAM_and_DNMT1_psychosis_2007" /> SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.{{citation needed|date=January 2016}}

Chromosome region [[7q22]] that harbours the ''RELN'' gene is associated with schizophrenia,<ref name="pmid17684500" /> and the gene itself was associated with the disease in a large study that found the polymorphism [[rs7341475]] to increase the risk of the disease in women, but not in men. The women that have the [[single-nucleotide polymorphism]] (SNP) are about 1.4 times more likely to get ill, according to the study.<ref name="pmid18282107" /> Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia.<ref name="pmid17684500" /> The association with working memory was later replicated.<ref name="pmid19922905" /> In one small study, nonsynonymous polymorphism [[Val997Leu]] of the gene was associated with left and right ventricular enlargement in patients.<ref name="pmid19054571" />

One study showed that patients have decreased levels of one of reelin receptors, [[VLDLR]], in the peripheral [[lymphocyte]]s.<ref name="pmid17936586" /> After six months of [[antipsychotic]] therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.<ref name="pmid17936586" />

Considering the role of reelin in promoting dendritogenesis,<ref name="Niu_2004" /><ref name="pmid18477607" /> suggestions were made that the localized dendritic spine deficit observed in schizophrenia<ref name="pmid18463626" /><ref name="pmid10632234" /> could be in part connected with the downregulation of reelin.<ref name="pmid10725376" /><ref name="pmid11592844" />

Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor [[NPAS3]], disruption of which is linked to schizophrenia<ref name="Kamnasaran_2003" /> and learning disability. Knockout mice lacking NPAS3 or the similar protein [[NPAS1]] have significantly lower levels of reelin;<ref name="Erbel-Sieler_NPAS3_deficient_mice_2004" /> the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene [[MTHFR]], with murine knockouts showing decreased levels of reelin in the cerebellum.<ref name="pmid15979267" /> Along the same line, it is worth noting that the gene coding for the subunit [[GRIN2B|NR2B]] that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition,<ref name="pmid17881522" /> stands as one of the strongest risk [[Candidate gene|gene candidates]].<ref name="GRIN2B_SZ_GENE_DB" /> Another shared aspect between NR2B and RELN is that they both can be regulated by the [[TBR1]] transcription factor.<ref name="pmid15066269" />

The [[Zygosity|heterozygous]] reeler mouse, which is [[Haploinsufficiency|haploinsufficient]] for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder,<ref name="HRM_shared_abnormalities_with_SZ" /> but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable.<ref name="HRM_not_SZ" />

As previously described, reelin plays a crucial role in modulating early neuroblast migration during brain development. Evidences of altered neural cell positioning in post-mortem schizophrenia patient brains<ref>{{cite journal | vauthors = Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE, Jones EG | title = Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients | journal = Archives of General Psychiatry | volume = 53 | issue = 5 | pages = 425–36 | date = May 1996 | pmid = 8624186 | doi=10.1001/archpsyc.1996.01830050061010}}</ref><ref>{{cite journal | vauthors = Joshi D, Fung SJ, Rothwell A, Weickert CS | title = Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia | journal = Biological Psychiatry | volume = 72 | issue = 9 | pages = 725–33 | date = November 2012 | pmid = 22841514 | doi = 10.1016/j.biopsych.2012.06.021 | s2cid = 8400626 }}</ref> and changes to [[gene regulatory network]]s that control [[cell migration]]<ref name=":1">{{cite journal|vauthors=Matigian N, Abrahamsen G, Sutharsan R, Cook AL, Vitale AM, Nouwens A, Bellette B, An J, Anderson M, Beckhouse AG, Bennebroek M, Cecil R, Chalk AM, Cochrane J, Fan Y, Féron F, McCurdy R, McGrath JJ, Murrell W, Perry C, Raju J, Ravishankar S, Silburn PA, Sutherland GT, Mahler S, Mellick GD, Wood SA, Sue CM, Wells CA, Mackay-Sim A|date=2010|title=Disease-specific, neurosphere-derived cells as models for brain disorders|journal=Disease Models & Mechanisms|volume=3|issue=11–12|pages=785–98|doi=10.1242/dmm.005447|pmid=20699480|doi-access=free|url=https://eprints.gla.ac.uk/85448/1/85448.pdf}}</ref><ref>{{cite journal | vauthors = Topol A, Zhu S, Hartley BJ, English J, Hauberg ME, Tran N, Rittenhouse CA, Simone A, Ruderfer DM, Johnson J, Readhead B, Hadas Y, Gochman PA, Wang YC, Shah H, Cagney G, Rapoport J, Gage FH, Dudley JT, Sklar P, Mattheisen M, Cotter D, Fang G, Brennand KJ | title = Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells | journal = Cell Reports | volume = 15 | issue = 5 | pages = 1024–1036 | date = May 2016 | pmid = 27117414 | pmc = 4856588 | doi = 10.1016/j.celrep.2016.03.090 }}</ref> suggests a potential link between altered reelin expression in patient brain tissue to disrupted cell migration during brain development. To model the role of reelin in the context of schizophrenia at a cellular level, olfactory neurosphere-derived cells were generated from the [[Nose|nasal]] [[Biopsy|biopsies]] of schizophrenia patients, and compared to cells from healthy controls.<ref name=":1" /> Schizophrenia patient-derived cells have reduced levels of reelin mRNA<ref name=":1" /> and protein<ref name=":2">{{cite journal | vauthors = Tee JY, Sutharsan R, Fan Y, Mackay-Sim A | title = Schizophrenia patient-derived olfactory neurosphere-derived cells do not respond to extracellular reelin | journal = npj Schizophrenia | volume = 2 | pages = 16027 | date = 2016 | pmid = 27602387 | pmc = 4994154 | doi = 10.1038/npjschz.2016.27 }}</ref> when compared to healthy control cells, but expresses the key reelin receptors and DAB1 accessory protein.<ref name=":2" /> When grown ''[[in vitro]]'', schizophrenia patient-derived cells were unable to respond to reelin coated onto [[tissue culture]] surfaces; In contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin.<ref name=":2" /> This work went on to show that the lack of cell migration response in patient-derived cells were caused by the cell's inability to produce enough [[focal adhesion]]s of the appropriate size when in contact with extracellular reelin.<ref name=":2" /> More research into schizophrenia cell-based models are needed to look at the function of reelin, or lack of, in the pathophysiology of schizophrenia.