Functional neuroimaging of genetic variation in serotonergic neurotransmission

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) is a potent modulator of the physiology and behavior involved in generating appropriate responses to environmental cues such as danger or threat. Furthermore, genetic variation in 5-HT subsystem genes can impact upon several dimensions of emotional behavior including neuroticism and psychopathology, but especially anxiety traits. Recently, functional neuroimaging has provided a dramatic illustration of how a promoter polymorphism in the human 5-HT transporter (5-HTT) gene, which has been weakly related to these behaviors, is strongly related to the engagement of neural systems, namely the amygdala, subserving emotional processes. In this commentary, we discuss how functional neuroimaging can be used to characterize the effects of polymorphisms in 5-HT subsystem genes on the response of neural circuits underlying the generation and regulation of mood and temperament as well as susceptibility to affective illness. We argue that in time, such knowledge will allow us to not only transcend phenomenological diagnosis and represent mechanisms of disease, but also identify at-risk individuals and biological pathways for the development of new treatments.Keywords: Amygdala, emotion, FMRI, PET, prefrontal cortex, serotonin Converging evidence from animal and human studies using a myriad of experimental approaches has revealed that serotonin is a critical neurotransmitter in the generation and regulation of emotional behavior (Lucki 1998). Serotonergic neurotransmission has also been an efficacious target for the pharmacological treatment of mood disorders including depression, obsessivecompulsive disorder, anxiety and panic (Blier & de Montigny 1999). Moreover, genetic variation in several key 5-HT subsystems, presumably resulting in altered central serotonergic tone and neurotransmission, has been associated with various aspects of personality and temperament as well as susceptibility to affective illness (Murphy et al. 1998;Reif & Lesch 2003). Although many of these findings have led to novel insights about the neurobiology of complex behaviors and psychiatric disease, the enthusiasm for their collective results has been tempered by weak, inconsistent and failed attempts at replication.The inability to substantiate these relationships through consistent replication in independent cohorts may simply reflect methodological issues such as inadequate control for non-genetic factors (e.g., age, sex and population stratification), insufficient power and/or inconsistency in the methods applied. Alternatively, and perhaps more importantly, such inconsistency may reflect the underlying biological nature of the relationship between allelic variants in serotonin genes, each of presumably small effect, and observable behaviors in the domain of mood and emotion that typically reflect complex functional interactions and emergent phenomena. Simply put, genes do not encode behaviors. Biology dictates that allelic variants will most likely have a functional impact on the cellular and molecular pathw...

A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1AReceptor Binding in Humans

“…A sample size of 35 subjects is a small number for a genetic study, but it is a large sample for a PET study and is consistent numerically with other recent neuroimaging studies showing plausible associations between polymorphisms and other imaging parameters such as functional magnetic resonance imaging responses to emotional face recognition (Hariri et al, 2002). Indeed, it has been suggested that emotional and affective neural systems, which can be imaged, may be more directly related to 5-HT functional polymorphisms than complex behaviors or psychiatric syndromes (Hariri and Weinberger, 2003). Although the validity of post hoc power calculations are debatable (Goodman and Berlin, 1994;Hoenig and Heisey, 2001), our power calculations showed that, for the 5-HT 1A receptor gene (Ϫ1018) CϾG SNP, we had a power of 89% to detect a 15% difference of BP between groups, with ␣ ϭ 0.05.…”

Toward a developmental neurobiology of autism

“…Interestingly, finding evidence for transmission of polymorphic alleles of the 5-HTT may depend on the extent of social and communication deficits in the autism proband, suggesting that the alleles may modify severity of autistic traits rather than conveying risk for autism per se [Tordjman et al, 2001]. Further support for 5-HTT comes from functional MRI studies showing that individuals with one or two copies of a short allele of the gene had greater neuronal activity than controls in the amygdala, a brain region implicated in autism [Hariri et al, 2002;Hariri and Weinberger, 2003]. In addition, multiple single polymorphisms in tryptophan 2,3 diooxygenase (TDO2), the rate-limiting enzyme in L-tryptophan catabolism, have been associated with autism.…”

COMT Val158Met polymorphism and socioeconomic status interact to predict attention deficit/hyperactivity problems in children aged 10–14

“…Indeed, several investigations including an 'oddball' task-generated P300 waveform study of healthy controls and patients with schizophrenia [24] suggest the presence of increased dopaminergic cortical signalling, enhanced signal/noise ratio, and optimized cortical activity, conferred by the Met allele, during processing tasks of different nature [18,25,39,47]. Two brain imaging studies of healthy adults showed an influence of the COMT Val158Met genotype on task-related brain activation.…”