Genetically dependent modulation of serotonergic inactivation in the human prefrontal cortex
Introduction
Serotonergic dysfunction within the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) is proposed as the core deficit in the pathophysiology of several psychiatric diseases characterized by aggressive and impulsive behaviour (Davidson et al., 2000, Frankle et al., 2005, Robbins, 2005). Reducing the concentration of serotonin (5-HT) by dietary tryptophan depletion in humans or selectively destructing the ascending serotonergic projections in animals strongly alters the OFC and ACC function (Park et al., 1994, Mobini et al., 2000, Clarke et al., 2004). Genetic variations, environmental factors and more complex genes by environment interactions have been associated with an increased risk to develop aggressive behaviour and other psychiatric disorders (Noblett and Coccaro, 2005, Caspi et al., 2002, Caspi et al., 2003). Although the underlying neurobiological mechanisms are still poorly understood, they may result from individual differences in the serotonergic neurotransmission within the OFC and ACC due, for instance, to genetically regulated variations in the inactivation of 5-HT (i.e. reuptake by the 5-HT transporter (5HTT) and breakdown by the monoamine oxidase-A (MAOA) enzyme).
Both MAOA and 5HTT genes present two well-characterized length-variable [i.e. variable number of tandem repeats (VNTR)] polymorphisms in their promoter regions that alter the transcriptional activity of the genes and hence the function of the corresponding proteins (Lesch et al., 1996, Sabol et al., 1998, Denney et al., 1999). The long variant of the MAOA polymorphism promotes a higher transcription of the gene [MAOA high-activity allele (MAOA-H)] which results in a higher activity of the enzyme when compared with the MAOA short variant [therefore defined as MAOA-low activity allele (MAOA-L)] (Sabol et al., 1998, Denney et al., 1999). The 5HTT gene presents an analogous VNTR polymorphism in the promoter region with short (5HTT-S) and long (5HTT-L) variants (Lesch et al., 1996). The analysis of lymphoblast cells demonstrated that the 5HTT-S allele resulted in a reduced serotonin uptake, lower serotonin receptor binding and lower mRNA concentration compared with the 5HTT-L allele (Lesch et al., 1996). Albeit different association studies have not consistently associated MAOA-H and 5HTT-S alleles with impulsive and aggressive behaviour or with other psychiatric disorders (Caspi et al., 2002, Caspi et al., 2003, Courtet et al., 2004, Baca-Garcia et al., 2004, Gerra et al., 2004), converging evidence suggests that these polymorphisms strongly regulate the serotonergic function in vitro and in vivo (Lesch et al., 1996, Sabol et al., 1998, Denney et al., 1999, Manuck et al., 2000, Manuck et al., 2002).
Functional imaging procedures that use the “endophenotypic approach” have began to show how genetic variations in the serotonergic molecular pathway modulate the neural circuits underlying the impulsive and aggressive behaviour (Congdon and Canli, 2005, Hariri et al., 2006a). A blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) study showed that MAOA-H carriers displayed a greater response of the anterior cingulate cortex (ACC) when compared with MAOA-L carriers during the execution of an attentional task (conflict resolution) (Fan et al., 2003). Other findings further demonstrated that the response of orbitofrontal cortex (OFC), elicited by a response inhibition paradigm (Go/NoGo), was increased in MAOA-H carriers (Passamonti et al., 2006). Finally, a recent work reported the profound impact of the MAOA polymorphism on different brain circuits involved in emotions, memory and cognitive control (Meyer-Lindenberg et al., 2006). Those authors showed a strong gender related difference, such that the ACC response during the execution of a cognitive control paradigm (response inhibition flanker task) was much greater in males carrying the MAOA-H allele.
Although both animal studies and imaging findings on humans also highlighted the impact of the 5HTT gene on the modulation of emotional circuits (Holmes et al., 2002, Hariri et al., 2002, Bertolino et al., 2005, Wellman et al., 2007), how MAOA and 5HTT genes might interact in the human brain remains unexplored. Comparative research indicates that these genes present combined and interplaying effects in regulating the metabolic pathway that leads to 5-HT inactivation (Murphy et al., 2003).
On the basis of these previous findings, we expected that MAOA and 5HTT genes might play an interactive role in modulating the serotonergic function, in particular in the OFC and the ACC, two cerebral regions presenting a high expression of the MAOA and 5HTT proteins (Fowler et al., 1987, Varnas et al., 2004) and a dense serotonergic innervation from the raphe nuclei (Clarke et al., 2004). To directly assess the individual and interactive contributions of the MAOA and 5HTT polymorphisms on brain responses, we studied healthy male volunteers using BOLD fMRI during the execution of a response inhibition task.
We hypothesized that individuals carrying simultaneously the allelic variants conferring a reduced serotonergic function (i.e. subjects carrying both the MAOA-H variant and at least one copy of the 5HTT-S allele) would display an increased BOLD response in the OFC and ACC compared with subjects presenting a genetically mediated higher serotonergic function (i.e. subjects carrying both the MAOA-L variant and homozygous for the 5HTT-L allele).
Section snippets
Subjects
Thirty-five right-handed healthy males (Caucasian, from southern Italy, age-range: 20–44 years) were recruited by local advertisements. Fifteen of them also participated in a previous study (Passamonti et al., 2006). We included only men for several reasons: (1) impulsive and aggressive behaviour is a typical male feature (Loeber and Keenan, 1994); (2) MAOA polymorphisms map in a region of the X chromosome suspected to escape the normal inactivation (Carrel et al., 1999); this makes it very
Results
The number of subjects for each genotype group, demographic data (age, educational level and IQ), trait impulsivity (as assessed by BIS-11 total score) and behavioural performances during the fMRI task are summarized in Table 1. In particular, the repeated measures of ANOVA did not show any statistically significant difference in all variables analyzed.
Consistent with previous reports (Liddle et al., 2001, Garavan et al., 2003), the main effect of the response inhibition in all subjects,
Discussion
This study provides new evidence that a significant interaction between MAOA-H and 5HTT-S impacts on the response of anterior cingulate cortex (ACC), as assessed by fMRI in a sample of healthy males. The highest BOLD activation in the ACC was found in individuals simultaneously carrying the MAOA high-activity variant (MAOA-H) and at least a copy of the 5HTT short allele (5HTT-S), both responsible of reduced serotonergic function in vivo (Manuck et al., 2000, Manuck et al., 2002, Whale et al.,
Acknowledgments
We thank Giuseppina Morganti and Andrea Fossati for contributions to early drafts of the manuscript.
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