Jennifer Taylor, Francois Feron,

Darryl Eyles, Jillanne Brown, Alan Mackay-Sim, Nicholas Hayward, Bryan Mowry,

John McGrath

Profiling the human transcriptome using

microarray technology offers an exciting opportunity to unravel the biology of

complex psychiatric disorders.  Gene expression analyses of post-mortem

brain tissue in schizophrenia have provided new leads for schizophrenia research

but have limitations due to unavoidable post-mortem changes.  Our group has

developed complementary approaches by applying microarray technology to human

fibroblast cultures obtained at biopsy and to an animal model of a putative risk

factor for schizophrenia.

Primary fibroblast cultures were

established for RNA extraction from 10 individuals with schizophrenia and 10

well controls.  Expression profiling was carried out using cDNAs arrays

constructed with the Human Unigene 4.5K set.  Generated data underwent

preprocessing, normalization and data mining procedures using GeneSpringä

Silicon Genetics.  Striking similarities were found with data generated

from post-mortem brain tissue.  As in post-mortem prefrontal tissue,

transcript dysregulation has been found for two neurotransmitters (GABA receptor

and glutamate transporter), a G protein regulator (RGS4), several interleukins

and other second messenger elements.  In addition, several misexpressed

transcripts suggest a role for pituitary hormones in schizophrenia. 

Data-mining has proposed the existence of several subtypes within the affected

sample, apparently driven primarily by variations in the GABAergic and

glumatergic neurotransmitter systems.

In parallel with the human study, we

examined gene expression in an animal model of a novel candidate risk factor for

schizophrenia (low prenatal vitamin D).  Rat pups born to vitamin

D-depleted mothers were depleted until birth, weaning or adulthood. 

Control rats had normal vitamin D intake.  At 10 weeks, mRNA was extracted

from brains (n=10/group) and analyzed using rate genome U34A arrays (8800 genes;

Affymetrix).  Gene expression was markedly dysregulated in the adult brain

of the “prenatally- depleted/ repleted-at-weaning” group, with

substantial down-regulation of mRNA transcripts for proteins involved in

neurotransmission (GABA receptor and glutamate transporter); synaptic function

(12 synaptic proteins); cytoskeleton maintenance (4 proteins); cell cycle

control (3 proteins); and signal transduction (4 signalling proteins).  In

animals that remain depleted until adulthood, we found a substantial

down-regulation of mRNA transcripts for prolactin, growth hormone and other

lactogen-related proteins.

Several transcripts are proposed for

further verification and candidate analysis on the basis that they appear to be

differentially expressed in human fibroblasts, animal studies and post-mortem

brain tissue studies.  We propose that the integration of data from

multiple sources has heuristic value in the interpretation of microarray studies

in schizophrenia.

The project was supported by the

Stanley Foundation.