The evolutionary history of SLC6A4 and the role of plasticity in Macaca.

Serotonin has been repeatedly indicated as a biological marker of behavior. In particular, the serotonin transporter gene, SLC6A4, has been the focus of a large body of research. Interestingly, both rhesus macaques (Macaca mulatta) and humans have independently evolved a number of shared polymorphisms for this gene, which is indicative of parallel evolution between the two species. However, little is known about the evolution of this gene, particularly within macaques. Although there are several hypotheses as to the adaptive values of various polymorphisms, few authors have gone beyond theoretical discussion. Here, we examined the genetic variation in SLC6A4 within and between several species of macaques and investigate whether selection has played a significant role in its evolutionary history. In addition, we assayed the promoter region polymorphism, 5-HTTLPR, which is known to play a significant role in regulating both serotonin turnover and behavior. In examining the distribution of the 5-HTTLPR polymorphism, we identified significant differences between Indian and Chinese populations of Macaca mulatta; furthermore, we discovered its presence in Macaca cyclopis, which has not been described before. In regard to the evolutionary history of SLC6A4, we found little evidence for selection and conclude that SLC6A4 largely evolved through neutral processes, possibly due to its potential role in regulating behavioral plasticity. However, we also found very low levels of linkage between the coding regions and 5-HTTLPR. Because we limited evolutionary analyses to the coding regions, it is possible that the promoter region shows a distinct evolutionary history from SLC6A4.

Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery.

Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule ("classical") neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new directions for future research.

Cerebral responses to emotional expressions and the development of social anxiety disorder: a preliminary longitudinal study.

BACKGROUND: Cross-sectional studies report biased reactivity to facial expressions among shy children, anxious adolescents, and adults with social anxiety disorder (SAD). It remains unknown whether cerebral reactivity to facial expressions can predict longitudinally the development of SAD in adolescence and characterize the degree of social anxiety among the general population of adolescents. METHODS: In a longitudinal study of 21 general population volunteers characterized for behavioral and genetic variables, N400 event-related potentials, and 3-Tesla fMRI activations in response to happy/neutral/angry expressions were acquired at age 8-9 and 14-15, respectively. RESULTS: By stepwise regression, N400 amplitudes acquired at age 8-9 predicted the number of DSM-IV SAD symptoms at age 14-15, with the sole, significant (P = .018) contribution of the "anger" condition. Factorial ANOVA revealed increased (Voxel-Level P((FWE)) range: .02-.0001) bilateral fMRI activations of several brain areas, including the amygdala, in response to facial expressions compared to a fixation cross. The number of symptoms of DSM-IV SAD was positively correlated with left amygdala response to angry (P((FWE)) = .036) and neutral (P((FWE)) = .025) facial expressions. Factorial ANOVA revealed that the 5-HTTLPR -S allele was associated with heightened left amygdala response to anger (P((FWE)) = .05). CONCLUSION: Cerebral reactivity to facial expressions, anger especially, measured at different developmental stages by different techniques is associated with adolescence SAD. The 5-HTTLPR genotype affects the neural processing of interpersonal affective stimuli during development.

Ancestry of neuronal monoamine transporters in the Metazoa.

Selective Na(+)-dependent re-uptake of biogenic monoamines at mammalian nerve synapses is accomplished by three types of solute-linked carrier family 6 (SLC6) membrane transporter with high affinity for serotonin (SERTs), dopamine (DATs) and norepinephrine (NETs). An additional SLC6 monoamine transporter (OAT), is responsible for the selective uptake of the phenolamines octopamine and tyramine by insect neurons. We have characterized a similar high-affinity phenoloamine transporter expressed in the CNS of the earthworm Lumbricus terrestris. Phylogenetic analysis of its protein sequence clusters it with both arthropod phenolamine and chordate catecholamine transporters. To clarify the relationships among metazoan monoamine transporters we identified representatives in the major branches of metazoan evolution by polymerase chain reaction (PCR)-amplifying conserved cDNA fragments from isolated nervous tissue and by analyzing available genomic data. Analysis of conserved motifs in the sequence data suggest that the presumed common ancestor of modern-day Bilateria expressed at least three functionally distinct monoamine transporters in its nervous system: a SERT currently found throughout bilaterian phyla, a DAT now restricted in distribution to protostome invertebrates and echinoderms and a third monoamine transporter (MAT), widely represented in contemporary Bilateria, that is selective for catecholamines and/or phenolamines. Chordate DATs, NETs, epinephrine transporters (ETs) and arthropod and annelid OATs all belong to the MAT clade. Contemporary invertebrate and chordate DATs belong to different SLC6 clades. Furthermore, the genes for dopamine and norepinephrine transporters of vertebrates are paralogous, apparently having arisen through duplication of an invertebrate MAT gene after the loss of an invertebrate-type DAT gene in a basal protochordate.