Reelin hypothesis of the development of Schizophrenia

Note: Please review this material, and the material in Talk:Schizophrenia by the same author marked "for review"'. See also see the speculative article How the pathology of schizophrenia relates to symptoms

No simple explanation of Schizophrenia is available. Please note that while the material below has a considerable evidence base there are many areas of conjecture.

What we do know: .

• There is a familial or genetic component.
• Despite there being a definite genetic component there must also be a environmental factor.
• Life-stresses do not cause schizophrenia but may precipitate an episode of psychosis.
• There is no simple or consistent genetic defect yet discovered.

How do we know there is a genetic component?

• If there is no family history a person has about 1:100 risk of schizophrenia.
• If you have a first degree relative there is about 1:10 risk.
• If you have an identical twin with schizophrenia the risk is about 40%.

How do we know there is an environmental factor?

Interestingly even with an identical twin the risk is not 100% therefore there must be some other factor.

It is thought that the perinatal or intra-uterine environment is important. This environment would be largely shared by an identical twin (blood supply may differ significantly however) and if anything the risk of an identical twin probably over-estimates the genetic risk.

Are there any definitely known causes in specific cases?

Yes. Syphilis, before Penicillin was the second commonest cause of Schizophrenia, as part of neurosyphilis. This form of schizophrenia differs from the more common idiopathic form because, in addition to the standard psychotic and delusional features there are other neurological symptoms.

The Velocardofacial syndrome or Di George syndrome is linked to a chromosomal deletion and this has a risk similar to that of an identical twin, probably indicating a full genetic susceptibility given this deletion.

Good general introduction to syndrome [[1] (http://www.nidcd.nih.gov/health/pubs_vsl/velocario.htm)] Better for schizophrenia implications) [[2] (http://info.med.yale.edu/chldstdy/plomdevelop/genetics/01aprgen.htm)]

The fragile X syndrome, a form of mental retardation,has a low but increased risk of schizophrenia. This is interesting because the fragile X protein is part of the Reelin system which is one of the proposed mechanisms of schizophrenia.

Paraphrenia, particularly paranoid form of schizophrenia occurring in the elderly as opposed to adolescents is thought to be caused by abnormalities in the tau protein, which is also linked to some cases of Alzheimers disease.

Given these genetic clues why cant we find a consistent genetic link?

I think the Reelin -integrin system is the most plausible explanation currently available for schizophrenia. This system controls neuro-development in the fetus and childhood and also controls neuroplasticity or adaptability in the mature brain. It is a complex system with many protein and many genes involved. We know in mouse models that damage to several different genes in the pathway cause similar outcomes (phenotypes). This would explain why a genetic link is consistent within a family but different families would have different defect on the pathway.

If Schizophrenia is genetic and is so devastating an illness why do the genetic faults persist?

This is a very puzzling problem. Throughout the world Schizophrenia affects about 1% of the population. It has a major effect on the fertility of the sufferer. Why doesn't it get selected out rapidly?

There are two possible explanations.

• If you don't have full blown schizophrenia the genotype may give you an evolutionary advantage.

OR

• The system is very complex involving many genes, increasing the chance of a mutation affecting this system. The disease is maintained by mutation.

The truth is probably a combination of both mechanisms. There is an anecdotal link between madness and genius (particulary mathematics music and the arts). It is hard to prove but the link is probably real.

What is the relationship of Schizphrenia with other forms of mental illness

I believe that schizophrenia has the same mechanism of neural damage as manic depression, or bipolar disease and schizo-affective disorder but that the mechanism is different to that of unipolar depression. This is supported by many family studies that show a schizophrenic patient is just as likely to have a bi-polar relative as schizophrenic relative. Vice versa for bi-polar patients. (In some studies the families breed true, however). This view is also supported by autopsy studies on psychotic brains.

The differences probably relate to site, timing and severity of the neuronal injury rather than there being different kinds of injury.

What about the non-genetic factors?

These are important and may even be more critical than a genetic predisposition.

What are the suggested possibilities:

1. Infection. I feel that this is the most likely factor. We know that syphilis can definitely, but not invariably, cause schizophrenia. Toxoplasmosis has been proposed (Torrey Fuller). Flavivirus has been suggested. Bornavirus has been suggested. Is the high susceptibily of Velocardiofacial syndrome due to deficient T cell immuno-difficiency or to neurodevelopmental effects?
2. .Vitamin D. Vitamin D deficiency has been proposed to account for the slight seasonal variation noted with more schizophrenics than expected having their gestation in Winter.
3. .Toxins. Heavy metals and other toxins have been proposed. These are plausible but tend to get more attention in alternative medical circles than conventional medicine.
4. Drugs. There is a reasonable evidence that drugs (particulary marijuana) can precipitate psychosis or perhaps lead to earlier schizophrenia than otherwise expected. I feel it is unlikely that they actually cause schizophrenia.

A conjecture as to the likely non-genetic component of schizophrenia

People usually contract schizophrenia in the period about 18-25. I think the most likely cause is a common virus causing encephalitis (such as an Echvirus or a type of cold virus). Nearly everybody would catch the virus and most people would catch this virus without ill-effect, perhaps no more than a headache.

On the other hand, if you are predisposed to schizophrenia (genetically) and catch the proposed virus during a relatively small time window of vulnerability, then you catch schizophrenia. The time window of vulnerability relates to the natural grey matter pruning of the brain (a normal neurodevelopmental happening) which occurs in the pre-frontal area at about the time time of susceptibility to Schizophrenia.

This would explain why:

• Not all genetically predisposed individuals get the disease.
• Nearly all cases start in late adolescence (the window of vulnerability).
• The disease distribution is uniform throughout the world.
• Atypical or non-idiophathic forms (eg syphilis and paraphrenia) may have a different time course.

If this postulate is true, it has the interesting corollary that the predisposed person may not be any different behaviourly to other people prior to the illness. The problem could well lie in an aberrant immune response.

An abnormal personality (schizoid) often occurs in schizophrenic patietns in the year or two before frank psychosis, and traditionally is is taught that there is a vulnerable schizoid personality type. However some recent studies have shown but there is no correlation between personality preceding this prodromal period (say 3 years or more before first pychosis) and any mental illness.

I suggest that the pathology is slowly progressive damage that starts during the prodrome.

External Links

Decreased reelin in schizophrenia and bipolar disorder

 [[3] (http://archpsyc.ama-assn.org/issues/v57n11/abs/yoa9104)]

Dendritic spine density in Schizophrenia

 [[4] (http://archpsyc.ama-assn.org/issues/v58n2/ffull/ylt0201-4)]

Wonderful site for neural microanatomy (Synapse web)

[[5] (http://synapses.bu.edu/index.asp)]

Reelin and Lissencephaly

[[6] (http://www.aesnet.org/currents_pdf/EPCreln.pdf)]

Good but very technical stuff on reelin mechanisms (including fruit fly):

[[7] (http://sdb.bio.purdue.edu/fly/cytoskel/disabl2b.htm)]

Pretty picture of Fragile X protein (no schizophrenia stuff)

[[8] (http://www.hhmi.org/news/warren)]

Long term potentiation (what is it?)

[[9] (http://www.psych.ualberta.ca/~mparent/Psyco_371_B1d/ltp371.htm)]

Good general introduction to Velocardiofacial syndrome [[10] (http://www.nidcd.nih.gov/health/pubs_vsl/velocario.htm)] Better for schizophrenia implications) [[11] (http://info.med.yale.edu/chldstdy/plomdevelop/genetics/01aprgen.htm)]