The heterozygote reeler mouse as a model for the development of a new generation of antipsychotics.
Neurochemical and structural prefrontal cortex abnormalities, including decreased reelin and glutamic acid decarboxylase (GAD)(67) expression, decreased thickness, increased neuronal packing density and decreased neuropil and dendritic spine number, are characteristics of schizophrenia neuropathology. Reelin is an extracellular matrix protein secreted by GABAergic interneurons that, acting through pyramidal neuron integrin receptors, provides a signal for dendritic spine plasticity. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression (mRNA and protein) replicate the dendritic spine and GABAergic defects described in schizophrenia. This genetic mouse model may be of value to reveal those GABAergic and integrin receptor signal transduction mechanisms that are likely to be downregulated by reelin deficiency in the brain of schizophrenia patients. An understanding of the epigenetic regulation of reelin gene expression and of the possible pathogenetic role of reelin deficiency in schizophrenia, may become a major focus that will open new avenues for the treatment of this disease.
Costa
Erminio
E
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, College of Medicine, 1601 West Taylor Street, Chicago, Illinois 60612, USA. costa@psych.uic.edu
Davis
John
J
Pesold
Christine
C
Tueting
Patricia
P
Guidotti
Alessandro
A
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000627:therapeutic use; D004195:Disease Models, Animal; D006580:Genetic Carrier Screening; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000235:genetics / Q000523:psychology*; D000091042:Reelin Protein; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse