Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome.
Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2).
Jurata
Linda W
LW
Psychiatric Genomics, Inc., 19 Firstfield Road, Gaithersburg, Maryland 20878, USA.
Gallagher
Paul
P
Lemire
Andrew L
AL
Charles
Vinod
V
Brockman
Jeffrey A
JA
Illingworth
Elizabeth Lindsay
EL
Altar
C Anthony
CA
D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D018891:Dentate Gyrus / Q000378:metabolism* / Q000503:physiopathology*; D004062:DiGeorge Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015723:Gene Library; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
D002394:Catechol O-Methyltransferase