The discovery that a common polymorphism (5-HTTLPR, short variant) in the human serotonin transporter gene (SLC6A4) can influence personality traits and increase the risk for depression in adulthood has led to the hypothesis that a relative increase in the extracellular levels of serotonin (5-HT) during development could be critical for the establishment of brain circuits. Consistent with this idea, a large body of data demonstrate that 5-HT is a strong neurodevelopmental signal that can modulate a wide variety of cellular processes. In humans, serotonergic fibers appear in the developing cortex as early as the 10th gestational week, a period of intense neuronal migration. In this study we hypothesized that an excess of 5-HT could affect embryonic cortical interneuron migration. Using time-lapse videometry to monitor the migration of interneurons in embryonic mouse cortical slices, we discovered that the application of 5-HT decreased interneuron migration in a reversible and dose-dependent manner. We next found that 5-HT6 receptors were expressed in cortical interneurons and that 5-HT6 receptor activation decreased interneuron migration, whereas 5-HT6 receptor blockade prevented the migratory effects induced by 5-HT. Finally, we observed that interneurons were abnormally distributed in the cerebral cortex of serotonin transporter gene (Slc6a4) knockout mice that have high levels of extracellular 5-HT. These results shed new light on the neurodevelopmental alterations caused by an excess of 5-HT during the embryonic period and contribute to a better understanding of the cellular processes that could be modulated by genetically controlled differences in human 5-HT homeostasis.

Suicide and depression are associated with an increased density of ␣ 2 -adrenoceptors (radioligand receptor binding) in specific regions of the human brain. The function of these inhibitory receptors involves various regulatory proteins (G i coupling proteins and G proteincoupled receptor kinases, GRKs), which work in concert with the receptors. In this study we quantitated in parallel the levels of immunolabeled ␣ 2A -adrenoceptors and associated regulatory proteins in brains of suicide and depressed suicide victims. Specimens of the prefrontal cortex (Brodmann area 9) were collected from 51 suicide victims and 31 control subjects. Levels of ␣ 2A -adrenoceptors, G␣ i1/2 proteins, and GRK 2/3 were assessed by immunoblotting techniques by using specific polyclonal antisera and the immunoreactive proteins were quantitated by densitometry. Increased levels of ␣ 2A -adrenoceptors (31-40%), G␣ i1/2 proteins (42-63%), and membrane-associated GRK 2/3 (24 -32%) were found in the prefrontal cortex of suicide victims and antidepressantfree depressed suicide victims. There were significant correlations between the levels of GRK 2/3 (dependent variable) and those of ␣ 2A -adrenoceptors and G␣ i1/2 proteins (independent variables) in the same brain samples of suicide victims (r ϭ 0.56, p ϭ 0.008) and depressed suicide victims (r ϭ 0.54, p ϭ 0.041). Antemortem antidepressant treatment was associated with a significant reduction in the levels of G␣ i1/2 proteins (32%), but with modest decreases in the levels of ␣ 2A -adrenoceptors (6%) and GRK 2/3 (18%) in brains of depressed suicide victims. The increased levels in concert of ␣ 2A -adrenoceptors, G␣ i1/2 proteins, and GRK 2/3 in brains of depressed suicide victims support the existence of supersensitive ␣ 2A -adrenoceptors in subjects with major depression. Key Words: ␣ 2A -Adrenoceptors-G proteins-G protein-coupled receptor kinase-Human brain-Suicide-Depression.

This publication updates the reference plasma and red blood cell protein maps obtained with immobilized pH gradients. Seventeen polypeptide spots or chains were partially characterized by direct N-terminal sequencing or by sequencing of peptides obtained from enzymatic digestion. Additional new polypeptides and previously known proteins are listed in a table and/or labeled on the protein maps, thus providing the 1993 update of the human plasma and red blood cell two-dimensional gel SWISS-2DPAGE database. SWISS-2DPAGE and the SWISS-PROT protein sequence databases are closely linked together through the use of common accession numbers.

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