Postmortem prefrontal cortices (PFC) (Brodmann's areas 10 and 46), temporal cortices (Brodmann's area 22), hippocampi, caudate nuclei, and cerebella of schizophrenia patients and their matched nonpsychiatric subjects were compared for reelin (RELN) mRNA and reelin (RELN) protein content. In all of the brain areas studied, RELN and its mRNA were significantly reduced (Ϸ50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia. To exclude possible artifacts caused by postmortem mRNA degradation, we measured the mRNAs in the same PFC extracts from ␥-aminobutyric acid (GABA) A receptors ␣ 1 and ␣ 5 and nicotinic acetylcholine receptor ␣ 7 subunits. Whereas the expression of the ␣ 7 nicotinic acetylcholine receptor subunit was normal, that of the ␣ 1 and ␣ 5 receptor subunits 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 putatively functioning as an intracellular target for the signaltransduction cascade 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 Purkinje neurons of schizophrenia patients, and nonpsychiatric subjects; these three types of neurons do not express RELN protein. In the same samples of temporal cortex, we found a decrease in RELN protein of Ϸ50% but 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. These findings are interpreted within a neurodevelopmental͞vulnerability ''twohit'' model for the etiology of schizophrenia.

Abstract:The effects of social isolation on behavior, neuroactive steroid concentrations, and GABA A receptor function were investigated in rats. Animals isolated for 30 days immediately after weaning exhibited an anxiety-like behavioral profile in the elevated plus-maze and Vogel conflict tests. This behavior was associated with marked decreases in the cerebrocortical, hippocampal, and plasma concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone compared with those apparent for group-housed rats; in contrast, the plasma concentration of corticosterone was increased in the isolated animals. Acute footshock stress induced greater percentage increases in the cortical concentrations of neuroactive steroids in isolated rats than in group-housed rats. Social isolation also reduced brain GABA A receptor function, as evaluated by measuring both GABA-evoked Cl Ϫ currents in Xenopus oocytes expressing the rat receptors and tert-[ 35 S]butylbicyclophosphorothionate ([ 35 S]TBPS) binding to rat brain membranes. Whereas the amplitude of GABAinduced Cl Ϫ currents did not differ significantly between group-housed and isolated animals, the potentiation of these currents by diazepam was reduced at cortical or hippocampal GABA A receptors from isolated rats compared with that apparent at receptors from group-housed animals. Moreover, the inhibitory effect of ethyl-␤-carboline-3-carboxylate, a negative allosteric modulator of GABA A receptors, on these currents was greater at cortical GABA A receptors from socially isolated animals than at those from group-housed rats. Finally, social isolation increased the extent of [ 35 S]TBPS binding to both cortical and hippocampal membranes. The results further suggest a psychological role for neurosteroids and GABA A receptors in the modulation of emotional behavior and mood.

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Social isolation of rats both reduces the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG) and 3a,5a-tetrahydrodeoxycorticosterone and potentiates the positive effects of acute stress and ethanol on the concentrations of these neuroactive steroids. We now show that social isolation decreased the plasma level of adrenocorticotropin (ACTH), moreover, intracerebroventricular administration of corticotropin releasing factor (CRF) induced a marked increase in the plasma corticosterone level in both isolated and group-housed rats, but this effect was significantly greater in the isolated rats (+121%) than in the group-housed rats (+86%). In addition, in isolated rats, a low dose of dexamethasone had no effect on the plasma corticosterone concentration, whereas, a high dose significantly reduced it; both doses of dexamethasone reduced plasma corticosterone in group-housed rats. Furthermore, the corticosterone level after injection of dexamethasone at the high dose was significantly greater in the isolated animals than in the group-housed rats. These results suggest that social isolation increased sensitivity of the pituitary to CRF and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis.

Post-weaning social isolation (SI) is a model of prolonged mild stress characterized by behavioral and neurochemical alterations. We used SI in C57BL/6J mice to investigate the effects of ethanol (EtOH) in the free-choice drinking paradigm on gene expression and function of γ-aminobutyric acid type A receptors (GABAARs) and the role of neuroactive steroids in the actions of EtOH in the hippocampus. SI stress induced a marked reduction in hippocampal 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABAAR. The gene expression of the α4 and δ subunits was increased in the hippocampus of SI C57BL/6J mice; the expression of the γ2 subunit was decreased whereas that of the α1 did not change. Patch-clamp recordings in dentate gyrus (DG) granule cells obtained from SI C57BL/6J mice revealed a greater enhancement of tonic currents induced by α-(4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) compared to that in control C57BL/6J mice. These neurochemical, molecular and functional changes observed in SI C57BL/6J mice were associated with an increased EtOH intake and EtOH preference. Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3α,5α-TH PROG induced by SI. EtOH self-administration blocked the changes in gene expression of the α4 subunit but not those of the δ and γ2 subunits induced by SI. In addition, EtOH self-administration did not block the SI-induced changes in GABAAR-mediated tonic inhibition in hippocampal granule cells but increased the frequency of basal GABAergic sIPSCs in DG granule cells. We conclude that self-administration of EtOH selectively abolishes the increase of α4 subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.

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