Talk:Reelin

(I moved this self-described conjecture from the original article here) Reelin and Schizophrenia Please note : THIS IS CONJECTURE NOT FACT.

I believe that schizophrenia is a clinical syndrome which is caused by reduced neuronal interconnectiviy and plasticity. The reduction of interneuronal connectivity could be:

1. non structural (eg drugs such as Ketamine, or metabolic defect),
2. structural with abnormalities caused by in Reelin, receptors or by abnormalities in the receptor complex.

The role of the Cajal Retzius cell, which secretes reelin, is interesting. Since it lies just below the pial surface (an area that is typically inflamed in syphilis) it may explain the appearance of schizophrenia in some cases of neurosyphilis. Death of this cell might also be a mechanism by which a viral meningitis or encephalitis could trigger Schizophrenia. (As far as I know there is NO EXPERIMENTAL EVIDENCE FOR THIS THEORY, but it seems plausible).

Refactored/stubified, replacing the entire text. Significant removed text which may be reincorporated as it is verified:

This exciting finding opens the possibility of explanation of at least some cases of schizophrenia and also the possibility of a useful animal model of the disease.

What does reelin do?

There are two main and probably distict roles:

1. It controls neuronal layering in the developing brain.
2. It regulates the growth of dendritic spines in the cortex and cerebellum.

NB: The information below has good experimental support. There will be numerous small errors of fact but the overall concepts are well founded.

The brain starts growth as a single layer of epithelium, thickens and then develops a single layer of neurones called the primary plate. Neurones then develop and move along a glial framework (a sort of microscopic neuroskeleton. The cells drop off at various points to form the 6 or so layers (variable from site to site ) of a normal adult neocortex. The act of dropping off is controlled by reelin. Without reelin neurones get stuck around the primary plate and normal layering is lost. Reelin is secreted by the Cajal Retzius cells which are a special type of nuerone found just below the pial or outside surface.

Human diseases that may be related abnormalities of this role of reelin include:

1. lissencephaly (smooth brain) associated with severe mental retardation.
2. Autism (some cases)

The second role of reelin controls neuroplasticity and uses the same molecular mechanisms as the neurodevelopmental functions. 1. Reelin is excreted into the extracellular space of the brain by Cajal Retzius cells near the brain surface. It seeps down to the middle pyramidal layer of the grey matter where pyramidal and intermediate neurones expresses reelin receptors. These receptors are similar to VLDL or cholesterol receptors. (This significance of this is uncertain but is interesting because of the relationship between ApoE3 and Alzheimers disease).

The stimulation of reelin then triggers a phosphokinase mechanism which encourages the production of mRNA and the production of actin. Actin is a "muscle protein" which then allows the neurone to actively alter its shape via "dendritic spines". The dendritic spines carry synapses which allow neurones to communicate with each other. (The synapses in the prefrontal cortex carry GLU or NDMA receptors). The phosphokinase receptor complex is a very large and complex molecule composed of several subunits. One subunit is the Fragile X protein. This is an abnormal protein that is associated with the commonest (known) from of inherited mental retardation and the Fragile X syndrome is also associated with an increased incidence of schizophrenia.

... end of removed text. Andrewa 19:44, 17 May 2004 (UTC)

I discovered reelin- there are many errors in this section- why not link to the original papers?

here is a great graphical illustration of the difference in corticogenesis between the "normal" and the "reeler" mice. Alas, as I understand, the image is copyrighted. But it is quite simple drawing. If somebody will re-draw the image and upload free version on the Reelin page, it would be great!--CopperKettle 16:35, 30 May 2006 (UTC)

1. Write in more detail about the DNMT1-induced hypermethylation of RELN promoter region (CpG islands)
2. Read on amphetamine-induced decrease in RELN expression.

--CopperKettle 17:38, 12 February 2007 (UTC)

1. Reelin pathway and.. pancreatic cancer --CopperKettle 05:53, 14 February 2007 (UTC)
2. NPAS3 is associated with schizophrenia; positioned inside the HAR21 region(Pollard 2006). HAR1 -\-, HAR3 -\-, and double mice knockouts display lowered reelin expression in the cortex. Strangely there is only one study dating back to 2004 though, and p-values seem rather high. --CopperKettle 12:22, 2 March 2007 (UTC)

I have to comment about the very excellent and heavily sourced information in the schizophrenia section, that some of it does have a sense of original research about it, could I clarify? E.g. the second paragraph seems to mix sentences and sources on animal model studies, with sentences and sources on human schizophrenia studies - do the sources themeslves make the links between them? Then "SAM, being a methyl group donor neccessary for DNMT activity, could further shift epigenetic control of gene expression" is unsourced, is that proposition being synthesized here? The fourth paragraph starts "Other interesting findings probably linking reelin pathway to developmental hypotheses of schizophrenia are noted in the studies on mice that..." who is saying that they probably link? "These data run in parrallel with the findings of increased risk of schizophrenia in humans" - who is saying they parallel them? Later "Considering the role of reelin in promoting dendritogenesis,[3][59] suggestions were made..." - the sources are different - did those making those suggestions consider that, or is the link just being made here? "Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is..." can I check, do all these examples make the link between reelin and risk genes themselves, or is that partly being made here? "Along the same line, it is worth noting that the gene coding for the subunit NR2B that is presumably affected by reelin in the process of NR2B->NR2A developmental change..." are the sources presuming that, or just here?

Different point - the significant reelin findings are cited up top, but the null findings separately further down. Wouldn't it be more NPOV to give a balanced indication up top that there have been inconsistent findings?

One other more incidental point, can I query the rationale for the lead describing schizophrenia and bipolar as "brain diseases"? I realise they are sometimes described in those terms, especially in neuroscience, but of course in many fields and in the DSM & ICD, they are classed as mental disorders. EverSince (talk) 20:56, 27 August 2008 (UTC)

Yes, the two "null finding" articles reporting no hypermethylation indeed should be mentioned furhter up; maybe the table of antipsychotic action could too be moved to the top of the section on "brain disease".

As to the possible original research - the implications: SAM in schizophrenia and reelin, NPAS3 and reelin, dendritogenesis and reelin, prenatal infection and reelin expression (parralleled in humans and mice; there exists a "psychosis dev. model" that is called "Maternal Immune Activation", MIA) - as far as I remember - are made in the published articles (see the "epigenetic hypothesis" at Schizophreniaforum.org by Costa et al) or in the recent book by Fatemi. Moreover, in the book there are links to dopamine pathway (with only one somewhat distant ref, so I do not mention it here yet) and more links to NMDAr.

I was unsure only about the NMDA developmental shift so I've looked up NR2A right now in the book - Costa et al discuss the fact in chapter 23 "Reelin Downregulation as a Prospective Treatment Target for GABAergic Dysfunction in Schizophrenia". They discuss it in the subsection on Heterosygous Reeler Mice as a partial schizophrenia model; yes, maybe it is proper to transfer this one finding to the reeler article. --CopperKettle (talk) 02:46, 28 August 2008 (UTC)

Well, if they are considered more strictly the "mental disorders", the section could be renamed; how about "role in neuropsychiatry" or something like that?

I'm planning to send letters to several reelin researchers so that they could weed out the wrong statements and maybe improve the article in other ways, if they want. --CopperKettle (talk) 02:46, 28 August 2008 (UTC)

Not sure about the section name, but I think the 2nd para of the article lead could be reworded a little to indicate the difference in classification of bipolar/schiz (and perhaps that the significant findings have not been found in all the studies?)

I don't know if the antipsychotics table should be moved up, but I agree that the general point should be covered in a paragraph on the range of findings and possible explanations. I noticed it has also been suggested that epigenetic differences may be a result of psychosis-induced neural changes?

I think it would help the general reader if the secondary sourcing as you've outlined it could in some way be gradually clarified within the article, so it's easier to see which citations are supporting which syntheses of the primary findings. Incidentally, just out of interest, the Schizophreniaforum article, which doesn't itself seem to be a peer-reviewed publication as such (but with an advisory board etc) seems to attribute what they call their novel hypothesis to an earlier journal article, Costa et al., 2002, which seems to be "Pharmacogenomics of schizophrenia: a proactive role for histone deacetylase inhibitors" but unlike the others they don't link to it and a quick search didn't turn it up on the journal website or pubmed/google. I may be getting mixed up somewhere... Cheers, EverSince (talk) 15:05, 28 August 2008 (UTC)

O.K., I'll try to refurbish the second para a bit. As to what goes first, the psychosis or the methylation and gene structure changes, it's very early to judge IMHO, the epigenetic research in psychiatry, it seems to me, just took up in recent 10 years or so. Costa and his colleagues have a row of papers on epigenetics of GAD67 and RELN in psychotic disorders, so there is no problem with publications in peer-researched journals; I linked to the SRF.org site because it's the most clear and fresh snapshot of this emerging hypothesis, which itself seems to be a part of the moving-and-changing-leading-edge of psychiatric epigenetics. I'll try to sort out the refs, like maybe moving the "implicating" ones closer to the verbs.. or giving a citation in the ref section below. Thanx for the advices, Ever! --CopperKettle (talk) 15:30, 28 August 2008 (UTC)

Oh I saw they'd authored many of the peer-reviwed articles too (and I think it's great to have the more accessible source in there), was just curious why couldn't find that one where they apparently earlier outlined their hypothesis. Very nice work building up the article btw... EverSince (talk) 23:24, 28 August 2008 (UTC)

Normalised the second paragraph a little. --CopperKettle (talk) 10:49, 4 September 2008 (UTC)

A note to myself:

• A polymorphic GGC triplet repeat located in the 5'-UTR region of RELN gene, which harbors in the normal population 8 to 10 repeats, is significantly increased in autistic patients to carry 4 to 23 additional repeat - find the source, maybe add to the "autism" section. --CopperKettle (talk) 13:08, 10 December 2008 (UTC)

These edits add some facts but also there is an additional claim that reelin-schizophrenia link is very weak; that may be, and I am all for the good "critique" paragraph, with sources or explanations why reelin may be a false lead. Best regards, --CopperKettle (talk) 15:29, 25 December 2008 (UTC)

I havent really understood this bit:

this result implied that they were receptors it was the later papers that demonstrated Reelin binding that confirmed this identity.

- did the paper was the first to acknowledge that VLDLR and ApoER2 are receptors? From the abstract, it seems that they are mentioned as receptors, as if it was already known. --CopperKettle (talk) 15:34, 25 December 2008 (UTC)

But as for the "Most scientists don't accept these inflated claims.", " this is not generally accepted." - these are very bold statements; there should be references at least to the blog or media publicatons. --CopperKettle (talk) 15:45, 25 December 2008 (UTC)

I quote: "In 1994 a new allele of reeler was obtained by insertional mutagenesis (Miao et al., 1994)". Is this the right phrasing? I do not fully understand that this means, maybe it should be rephrased or the terms wiki-linked to appropriate articles for further "self-study". --CopperKettle (talk) 02:44, 26 December 2008 (UTC)

• A quote from the article:

  One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients.[109]

  - but HDAC1 may be protective against injury:^[1]

  "Indeed, reducing HDAC1 activity using small interfering RNA or a specific inhibitor in cultured cortical neurons or in vivo resulted in increased numbers of DNA double strand breaks (DSBs), the expression of cell cycle proteins and cell death. Increasing HDAC1 function by overexpressing it had the opposite effect, protecting cells against DSBs and neurotoxicity."

  Hmm.. what if HDAC1 increase is the brains' reply to toxic medication.. --CopperKettle 04:58, 16 February 2009 (UTC)

The addition by User:DavidJWu seems to be too extensive and a bit loosely related (IMHO):

Kanner in 1943 was the first to report on the neurological disorder autism and among his many observations he noticed that a portion of his cohort had enlarged heads.^[2] This observation of macrocephaly was corroborated by numerous studies and some suggest that accelerated growth is an early warning sign of risk of autism.^[3][4][5][6] These studies led researchers to examine the neurophysiology of autistic subjects. However, the small research sample sizes lead to a lack of statistical power compounded with the natural heterogeneity of the disorder introduced many confounding variables that have made results inconclusive. What has been concluded thus far is that there is a decrease number of Purkinje cells throughout the cerebellum and cortical dysgenesis reminiscent of the reeler mouse.^[7]

In 2002, Fatemi et al. measured the blood levels of unprocessed Reelin in 28 autistic twins, their parents and siblings. A statistically significant reduction of the unprocessed Reelin was found in the twins along with their parents and even unaffected siblings when compared to controls.^[8] Despite the inconclusive neuropathology studies, some abnormalities were reminiscent of the reeler neuropathology and the identification of reduced Reelin levels by Fatemi et al. led to the genomic screening of reelin.

Autistic family and twin studies have suggested that genetic factors might lead to a predisposition of autism.^[9] The proposition by many is that reelin is one of those candidate genes for autism. Studying 95 autistic subjects, Itailian in ethnicity, and 186 matched controls, there was a significant association with a polymorphic repeat located immediately preceding the 5’ ATG initiator codon of reelin.^[10] Longer triplet repeats in the 5’ region were associated with an increase in autism susceptibility. The 5’ end of reelin was further analyzed using 125 multiple-incidence families. There was no significant difference between the length of repeats found between affected and controls however, family based association test found that larger reelin alleles were transmitted more frequently than expected to affected children^[11].

• Why is there a whole paragraph on large heads?
• Fatemi et al., 2002 is already cited by me above
• After that comes the second mention of "abnormalities reminiscent". Could be merged into one, IMHO
• General mention of genetic factor of autims could be dropped, and a "main article" template leading to the Heritability of autism article could be added to the subsection instead.

Best regards, --CopperKettle 13:54, 1 June 2009 (UTC)

That whole section was way too long as a summary of Reelin and autism. Also, it cited primary studies, where it should be citing reliable reviews (as per WP:MEDRS). I took a crack at the problem by rewriting the section to make it briefer and to cite a reliable review, Pardo et al. 2007 (PMID 17919129). Eubulides (talk) 20:52, 1 June 2009 (UTC)

I like the summary but I would like to expand on the triplet polymorphism --DavidJWu (talk) 05:44, 2 June 2009 (UTC)

Reviewer: Tea with toast (talk • message • contribs • count) 22:58, 1 September 2011 (UTC)

GA Review

This review is transcluded from Talk:Reelin/GA1. The edit link for this section can be used to add comments to the review.