A decrease of reelin expression as a putative vulnerability factor in schizophrenia

Postmortem prefrontal cortices (PFC) (Brodmann's areas 10 and 46), temporal cortices (Brodmann's area 22), hippocampi, caudate nuclei, and cerebella o f schizophrenia patients and their matched nonpsychiatric subjects were com pared for reelin (RELN) mRNA and reelin (RELN) protein content. In all of t he brain areas studied, RELN and its mRNA were significantly reduced ( appr oximate to 50%) in patients with schizophrenia; this decrease was similar i n patients affected by undifferentiated or paranoid schizophrenia. To exclu de possible artifacts caused by postmortem mRNA degradation, we measured th e mRNAs in the same PFC extracts from gamma-aminobutyric acid (GABA)(A) rec eptors alpha(1) and alpha(5) and nicotinic acetylcholine receptor alpha(7) subunits. Whereas the expression of the alpha(7) nicotinic acetylcholine re ceptor subunit was normal, that of the alpha(1) and alpha(5) receptor subun its of GABA(A) was increased when schizophrenia was present. RELN mRNA was preferentially expressed in GABAergic interneurons of PFC, temporal cortex, hippocampus, and glutamatergic granule cells of cerebellum. A protein puta tively functioning as an intracellular target for the signal-transduction c ascade triggered by RELN protein released into the extracellular matrix is termed mouse disabled-1 (DAB1) and is expressed at comparable levels in the neuroplasm of the PFC and hippocampal pyramidal neurons, cerebellar Purkin je neurons of schizophrenia patients, and nonpsychiatric subjects; these th ree types of neurons do not express RELN protein. In the same samples of te mporal cortex, we found a decrease in RELN protein of approximate to 50% bu t no changes in DAB1 protein expression. We also observed a large (up to 70 %) decrease of GAD67 but only a small decrease of GAD65 protein content. Th ese findings are interpreted within a neurodevelopmental/vulnerability "two -hit" model for the etiology of schizophrenia.