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Reelin

Reelin, neurodevelopment and neural plasticity.

(Please note this material needs review and is currently written from memory. I will proof read and reference when I have my written reference material available).

"Reeler" mice, known as such because of there abnormal gait were shown to have a deficiency of brain protein called reelin and were homozygous for the Reelin gene. Heterozygous mice for the reelin gene had very little obvious neuroanatomical defect but those that they had resembled the changes of the human schizophrenic brain. A special stain for the reelin protein show a similar pattern of reelin deficiency in heterozygotic reeler mice and in biopsies of brains of pyschotic patients.

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.

1. Brain Layering.

The brain starts growth as a single layer of epithelium, thickens and then develops a single layer of nuerones 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.

Reelin and Schizophrenia Please note : THIS IS CONJECTURE NOT FACT.

I believe that schizophrenia is a clinical syndrome which is caused by reduced neuronal interconnnectiviy 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).

 



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