Reelin and GAD67 Downregulation

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DESCRIPTION: (provided by applicant) Reelin (Rein) is a glycoprotein, which in adult neocortex is preferentially fotmed and secreted y y-aminobutyric acid (GABA) secreting horizontal and double-bouquet intemeurons of layers I/il, and is mainly located in the extracellular matrix (ECM) surrounding apical dendrites and spines of cortical pyramidal neurons (layers ffl-V). The expression of Rein and glutamic acid decarboxylase 67 (GAD67), but not the disabled-I -gene product (DAB 1), are downregulated in schizophrenia postmortem brains (Appendix X). To verify whether other psychiatric disorders express similar deficits, we analyzed, blind, a new cohort of 60 postmortem brains including equal numbers of patients matched for schizophrenia (S), unipolar depression without psychosis (UD). and bipolar disorders with (BDP) or without (BD) psychosis with nonpsychiatric subjects (NP). The number of Rein-positive cells in the prefrontal cortex (PFC) as well as Rein and GAD67 mRNAs and proteins were decreased by 30 to 50 percent in S and BDP patients but not in UD when compared with NP. Group differences were absent for DAB1, GAD65 and neuronal-specific enolase (NSE) expressions, implying that no decrease of neuronal expression or damage occurred. Rein and GAD67 downregulation were unrelated to postmortem interval, pH, dose, duration, or presence of antipsychotics. In heterozygous reeler+/- mice, we found a downregulation of Rein and GAD67 mRNA expression and of dendritic spine density in pyramidal neurons of layer III. The expressions of GAD67 and Rein mRNAs were correlated in the PFC of NP and UD, and wild-type mouse frontal cortex but not S, BDP, or heterozygous RELN+/-. HYPOTHESIS: When a psychiatric disorder includes a psychotic component, the correlation between Rein and GAD67 mRNA expression existing in nonpsychotic and nonpsychiatric patients failed to be expressed. This hypothesis will be addressed with four aims: 1) to study the expression of GAD67, Reln, NSE. DAB 1. GAD65, and neuronal-specific a integrin subunit mRNAs and their correlations in other cortical areas of the above-mentioned diagnostic cohorts; 2) to study the parameters mentioned in Aim lin other diagnostic cohorts, including S, UDP, and BD patients and NP subjects in 5 cortical areas and cerebellum; 3) to study the Rein and GAD67 mRNAs and Rein-positive neuron expression in the frontal, temporal, cingulate, and visual cortex of 3 nonhuman primates, and to determine subcellular location of Rein and verify its colocation with a3 integnn receptor subunits; and 4) to study mechanistically in heterozygous Reln+/- and the GAD67 KO (GAD67+/-) whether GAD67 and Rein mRNA downregulations are a cause of dendritic spine density downregulation.