How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure

A Kobiella,S Vollstädt-Klein,A Heinz,M Rietschel,C Vollmert,G Reischl,D E Ulshöfer,M Reimold,M N Smolka,V N Ikonomidou

doi:10.1038/tp.2011.29

A Kobiella, S Vollstädt-Klein + Show 8 more

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https://doi.org/10.1038/tp.2011.29

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The serotonin transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene is associated with amygdala response during negative emotion. The aim of this study was to investigate whether this genotype effect on amygdala function is mediated by current serotonin transporter (5-HTT) levels or rather by genetically induced influences during neurodevelopment, shaping brain structure. A total of 54 healthy subjects underwent functional and structural magnetic resonance imaging, [11C]DASB positron emission tomography and 5-HTTLPR genotyping to analyze the interrelationships between amygdala activation during processing of unpleasant stimuli, 5-HTTLPR genotype, amygdala volumes and 5-HTT levels in the midbrain and in other brain regions. In line with previous research, carriers of the short allele (S) showed increased amygdala activation. Path analysis demonstrated that this genotype effect was not procured by current 5-HTT availability but by amygdala structure, with smaller amygdala volumes in the S than in the LL genotype, as well as smaller volumes being associated with increased amygdala activation. Our findings stress the role of genetic effects during neurodevelopment.

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Serotonin (5-HT) neurotransmission has a key role in stress sensitivity and in vulnerability to negative affect.[1,2] The serotonin transporter gene (SLC6A4) encodes the serotonin transporter protein (5-HTT), which acts as a key regulator by removing serotonin from the synaptic cleft
Frequencies did not differ significantly from the Hardy–Weinberg equilibrium (w2 1⁄4 0.46; P 1⁄4 0.50). 5-HTT availability was highest in the midbrain, thalamus, amygdala and striatum (Supplementary Figure S2)
Midbrain 5-HTT availability was highly associated with thalamic 5-HTT availability (r 1⁄4 0.84, Po0.001) and amygdala 5-HTT availability (r 1⁄4 0.67, Po0.001)

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Serotonin (5-HT) neurotransmission has a key role in stress sensitivity and in vulnerability to negative affect.[1,2] The serotonin transporter gene (SLC6A4) encodes the serotonin transporter protein (5-HTT), which acts as a key regulator by removing serotonin from the synaptic cleft. A variation in the promoter region of SLC6A4, serotonin transporter-linked promoter region (5-HTTLPR), influences its transcriptional activity and regulates 5-HTT expression and density in human cell lines.[1,3,4] The 5-HTTLPR is a repeat polymorphism with long (L) and short (S) alleles. The recently discovered A/G single-nucleotide polymorphism (rs25531) within the length polymorphism led to the distinction between the variants LA and LG, with the latter one found to be functionally similar to the S allele.[5,6] As the rs25531 G allele is almost always in phase with the L allele,7 5-HTTLPR is often considered a triallelic polymorphism (LA, LG and S)

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