Decrease in reelin and glutamic acid decarboxylase(67) (GAD(67)) expression in schizophrenia and bipolar disorder - A postmortem brain study

Background: Reelin (RELN) is a glycoprotein secreted preferentially by cort ical gamma -aminobutyric acidergic (GABAergic) interneurons (layers I and I I) that binds to integrin receptors located on dendritic spines of pyramida l neurons or on GABAergic interneurons of layers III through V expressing t he disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediate s RELN action. To replicate earlier findings that RELN and glutamic acid de carboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schiz ophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmort em brains, including equal numbers of patients matched for schizophrenia, u nipolar depression, and bipolar disorder with nonpsychiatric subjects. Methods: Reelin, GAD(65), GAD(67), DAB1, and neuron-specific-enolase messen ger RNAs (mRNAs) and respective proteins were measured with quantitative re verse transcriptase-polymerase chain reaction (RT-PCR) or Western blot anal yses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. Results: Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significant ly decreased by 30% to 50% in patients with schizophrenia or bipolar disord er with psychosis, but not in those with unipolar depression without psycho sis when compared with nonpsychiatric subjects. Group differences were abse nt for DAB1,GAD(65) and neuron-specific-enolase expression implying that RE LN and GAD(67) down-regulations were unrelated to neuronal damage. Reelin a nd GAD(67) were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. Conclusions: The selective down-regulation of RELN and GAD(67) in prefronta l cortex of patients with schizophrenia and bipolar disorder who have psych osis is consistent with the hypothesis that these parameters are vulnerabil ity factors in psychosis; this plus the loss of the correlation between the se 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.