Reelin down-regulation in mice and psychosis endophenotypes.
Reelin, a large glycoprotein secreted by telencephalic GABAergic neurons, plays an important role in neuronal guidance embryonically and in synaptic plasticity postnatally. The reeler heterozygous mouse (+/rl) appears superficially normal but has been of interest as an animal model for psychosis since the discovery that reelin is 50% down-regulated in postmortem psychotic brain. Brain abnormalities in +/rl are similar to psychotic brain and include a reduction in glutamic acid de carboxylase 67 (GAD67), dendritic arbors and spine density in cortex and hippocampus, and abnormalities in synaptic function including long-term potentiation (LTP). In spite of these abnormalities, behavioral abnormalities in +/rl are subtle and controversial. Recent findings indicate that the reelin (RELN) and GAD67 promoters are hypermethylated in GABAergic neurons of psychotic postmortem brain and that DNA methyltransferase 1 (DNMT1) is up-regulated. Hypermethlyation of RELN and GAD67 promoters can be induced by treating mice with methionine, and these mice display brain and behavioral abnormalities similar to +/rl. Thus, an animal model that combines genetic heterozygocity with epigenesis holds promise for understanding the role of Reelin down-regulation in psychosis.
Tueting
Patricia
P
Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street Chicago, IL 60612, USA. ptueting@psych.uic.edu
Doueiri
Mohemed-Salim
MS
Guidotti
Alessandro
A
Davis
John M
JM
Costa
Erminio
E
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010641:Phenotype; D011618:Psychotic Disorders / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D005680:gamma-Aminobutyric Acid; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1