Decrease in Reelin and Glutamic Acid Decarboxylase67 (GAD67) Expression in Schizophrenia and Bipolar Disorder

TLDR

Reelin is a glycoprotein secreted by cortical GABAergic interneurons that binds integrin receptors on dendritic spines of pyramidal neurons and other interneurons, a process mediated by the adaptor protein DAB1. The study aimed to replicate prior findings of reduced RELN and GAD67 expression in schizophrenia and to determine whether similar deficits occur in bipolar disorder and unipolar depression by analyzing a new, blind cohort of 60 postmortem brains matched to nonpsychiatric controls. Researchers quantified RELN, GAD65, GAD67, DAB1, and neuron‑specific enolase mRNAs and proteins using quantitative RT‑PCR and Western blot, and identified Reelin‑positive neurons by immunohistochemistry with a monoclonal antibody. RELN and GAD67 mRNA and protein levels in the prefrontal cortex were decreased by 30–50 % in schizophrenia and bipolar disorder with psychosis, while DAB1, GAD65, and NSE expression remained unchanged, indicating that RELN and GAD67 down‑regulation is specific to psychosis and unrelated to postmortem interval, medication, or disease duration.

Abstract

<h3>Background</h3> Reelin (RELN) is a glycoprotein secreted preferentially by cortical γ-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)₆₇, but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. <h3>Methods</h3> Reelin, GAD₆₅, GAD₆₇, DAB1, and neuron-specific–enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. <h3>Results</h3> Prefrontal cortex and cerebellar expression of RELN mRNA, GAD₆₇protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD₆₅and neuron-specific–enolase expression implying that RELN and GAD₆₇down-regulations were unrelated to neuronal damage. Reelin and GAD₆₇were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. <h3>Conclusions</h3> The selective down-regulation of RELN and GAD₆₇in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.