Resumen de Diferencias del metabolismo en estructuras límbicas de acuerdo a la variación alélica del polimorfismo 5HTTLPR del gen al transportador de serotonina: un estudio piloto con PET
- español
El sistema serotoninérgico es considerado como uno de los principales sistemas involucrados en el desarrollo de diversos trastornos psiquiátricos. El gen en humanos que codifica para el transportador de serotonina (5HTT) se denomina SLC6A4 y se encuentra localizado en el cromosoma 17q12.2.Se ha descrito un polimorfismo funcional en la región promotora del gen (5HTTLPR), el cual confiere una actividad transcripcional diferencial alelo-dependiente, determinada por sus dos variantes alélicas: larga o L y corta o S. Desde la perspectiva conductual, se ha asociado a los individuos portadores del alelo S con una mayor susceptibilidad para presentar trastornos del afecto, personalidad con rasgos ansiosos y aumento en la respuesta condicionada al miedo.
Estudios in vivo en humanos, para cuantificar los sitios de unión al 5HTT han mostrado una menor disponibilidad del 5HTT en el rafé mesencefálico de sujetos portadores del alelo S. Sin encontrar diferencias en regiones corticales. Asimismo, se ha encontrado una mayor reactividad amigdalina, ante estímulos afectivos, en los portadores del alelo S. Hasta el momento, ningún estudio ha evaluado las diferencias en el metabolismo cerebral basal de acuerdo al genotipo HTTLPR. El objetivo de este estudio fue comparar la actividad metabólica basal mediante Tomografía por Emisión de Positrones (PET) entre sujetos homocigotos al alelo funcional S o L. Esto para determinar las regiones con mayor o menor metano lismo (actividad) de acuerdo a la variante alélica. Se incluyeron 14 sujetos sin enfermedad psiquiátrica (criterios DSM-IV) a los cuales se les realizó un PET cerebral con (18) F-fluorodeoxiglucosa. Todos fueron genotipados para el gen HTTLPR. Las imágenes de PET de los sujetos S/S (n=8) y L/L (n=6) se seleccionaron para su comparación voxel a voxel mediante un análisis de covarianza. Se utilizaron como covariables la puntuación de las subescalas de ansiedad y depresión del SCL-90. Se consideró a priori como significativas aquellas regiones límbicas con una p-corregida <0.01 con al menos 10 voxeles por grupo (clusters). Además se realizó un análisis de conectividad en donde se correlacionó (coeficiente de Pearson) el metabolismo regional entre las áreas cerebrales límbicas con mayores diferencias en el análisis de covarianza.
Las regiones en donde el grupo S/S presentó un metabolismo mayor que el grupo L/L son: Giro fusiforme izquierdo y derecho, lóbulo anterior del cerebelo izquierdo, parietal superior derecho y cíngulo posterior derecho, cíngulo anterior izquierdo, cuerpo del núcleo caudado izquierdo, giro frontal superior izquierdo y derecho, giro frontal inferior derecho, amígdala temporal izquierda y derecha, giro temporal superior izquierdo. Por otro lado las regiones en donde el grupo L/L presentó mayor metabolismo con respecto al S/S son: giro frontal medio izquierdo y giro frontal superior derecho. El análisis de conectividad entre estructuras límbicas presentó coeficientes de correlación más elevados en el grupo S/S en comparación al L/L.
Nuestros resultados muestran la presencia de diferencias en el metabolismo basal entre los sujetos homocigotos al alelo S y L.El análisis de conectividad muestra mayor acoplamiento en la actividad metabólica de las estructuras límbicas en los sujetos homocigotos al alelo S. Esto pudiera explicar la mayor susceptibilidad de los S/S para presentar trastornos del espectro depresivo-ansioso. Se propone un posible endofenotipo (metabolismo cerebral) asociado a la expresión de las variantes alélicas del 5-HTTLPR que podría servir como marcador de susceptibilidad para los trastornos que se han asociado a este genotipo.
- English
Serotoninergic neurotransmitter system seems to be a promising candidate for a biological marker in psychiatry since has been involved in the pathogenesis of various neuropsychiatry disorders, like affective disorders. The target site of action of some antidepressant drugs such fluoxetine is the serotonin (5HT) transporter (5HTT). The function of 5HTT is the reuptake of the serotonin released in the synaptic cleft and determines the magnitude and duration of the postsynaptic receptor-mediated signaling, thus playing a pivotal role in the fine-tuning of 5HT neurotransmission. A functional polymorphism in promoter region of the 5HTT(5HTTLPR) gene (SLC6A4) has been shown to modulate the 5HTT reuptake capacity, brain 5HTT binding sites and 5HTT mRNA quantity. The activity of the promoter region of the 5HTT gene is dependent of two allelic variants (long; L and short; S). Cultured lymphoblast homozygous for the L allele (L/ L) has higher concentration of 5HTT mRNA and express nearly twofold greater 5HT reuptake compared with cells with either one (L/S) or two copies (S/S) of the S allele. In vivo human brain studies quantifying binding levels of 5HTT using SPECT have shown heterogeneous results between L/L, L/S or S/S carriers. Control S carriers subjects have less available 5HTT in the raphe than homozygous to L allele. No differences in the diencephalons, thalamus, hypothalamus and mesencephalonpons regions have been shown. Behavioral studies have associated individual’s carries of S allele more likely to present mood disorders, anxiety-related personality traits, acquired conditioned fear responses and impulsive behavior. Functional brain imaging techniques have frequently implicated in the processing of these behaviors and disorders fronto-cortical and limbic structures. Recently has been explored the functional temporal amygdala neural activity, assessed by functional magnetic resonance imaging, in response to fearful stimuli in healthy subjects. Those carriers of S allele exhibit greater amygdale activity. To our knowledge, no study, has evaluated the differences of basal brain metabolism among the HTTLPR genotype. The propose of this preliminary study, was to compare the basal metabolic activity, obtained by positron emission tomography (PET), in fronto-cortical and limbic structures of non-psychiatric patients, to sustain differences in the basal neural activity among homozygous to this functional polymorphism.
In this study we performed PET scans with (18)Ffluorodeoxyglucose (FDG) as radiotracer in 14 non-psychiatrically ill individuals (screened by SCID-I, RV). All subjects were genotyped for the SLC6A4. The comparison groups were constituted as follows: S/S (n=8) vs. L/L (n=6). The analysis of PET images was performed using SPM2 software considering as significant only those limbic regions with a p-corrected < 0.01 and cluster of at least 10 voxels. In a secondary analysis a correlation between the metabolic activity of the areas with main differences among groups were performed. We found a significant increase of brain metabolism in those S/S individuals vs. L/L homozygous subjects in the following areas: left and right Fusiform Gyrus (Brodmann Area (BA) 37 and 19 respectively) (T = 5.11, p < 0.001; T = 5.05, p < 0.001 respectively). Left anterior cerebellum (T = 5.70, p < 0.001). Right superior Parietal and right posterior Cingulate (BA 7 and 31) (T = 8.03, p < 0.001 both). Left anterior Cingulate (BA 42) (T = 3.04, p < 0.01). Left Caudate (T = 4.03, p < 0.001). Left and right superior Frontal Gyrus (AB 8 and 9) (T = 3.66, p < 0.01 and T = 4.54, p < 0.001, respectively). Right inferior Frontal Gyrus (BA 47) (T = 4.47, p < 0.001). Right and left Amygdale (BA 38) (T = 4.16, p < 0.001 and T = 3.75, p < 0.01, respectively). Left superior Temporal Gyrus (BA 29) (T = 3.82, p < 0.01). In contrast those areas where we found an increased metabolism of those L/L individuals vs. S/S were: Left middle Frontal Gyrus (BA 8 and 9) (T = 3.38, p < 0.01) and right superior Frontal Gyrus (BA 9) (T = 2.93, p < 0.01). The correlation analysis showed higher correlation coefficients among limbic structures in the S/S groups than in the L/L group. Right Amygdale - Left Amygdale (S/S = 0.541 vs. L/L = 0.101); Left Amygdale – Left anterior Cingulate (S/S = 0.722 vs. L/L = 0.475); Left anterior Cingulate – Right posterior Cingulate (S/S = 0.720 vs. L/L = -0.094); Right Amygdale – Left anterior Cingulate (S/S = 0.867 vs. L/L = 0.610); Right Amygdale – Right posterior Cingulate (S/S = 0.586 vs. L/L = -.246). Our results shows differences in basal metabolism between homozygous individuals to alleles S and alleles l of the 5HTTLPR. A major basal metabolism in limbic system, like anterior and posterior cingulate and amygdale, and also other structures like fusiform gyruses, dorsolateral prefrontal cortex and superior temporal cortex was found in homozygotes to S allele. On the contrary, homozygote subjects to L allele presented a greater metabolism on bilateral frontal structures. The selective increase in basal metabolism found in our results could reflect an “hiperexcitability state” of these structures, with a larger repercussion to stimulus with an emotional meaning in S/ S subjects in comparison to the L/L ones. This would support a major susceptibility in these subjects to develop an anxietydepression spectrum disorder. The observed correlation between regions, shows a greater functional coupling (connectivity) between limbic structures (both amygdales, anterior and posterior cingulate) in S/S in comparison to L/L subjects. There is also a correlation between limbic and cortical structures (frontal, bilateral and left fusiform). This could explain that, in S/S individuals, any sensorial afference could induce an important effect on structures involved in emotional processing (frontal and limbic) making, these individuals prone to the development of affective disorders. Both, the structure and the global cerebral functioning (endophenotypes) are determined by interactions between genetic information and environment. However, genes can determine or promote a conduct in some environments, specially if we consider that they can promote susceptibility for some conduct (intelligence, personality traits, psychopathology, etc). The study of the association between a “determined brain metabolism” or endophenotype and an allelic variant (gene), can contribute to know more about the susceptibility of an individual to develop a determined conduct or disorder. Our results could propose an endophenotype (cerebral metabolism) associated with the expression of the allelic variants of the 5-HTTLPR that could be a useful marker of susceptibility for the disorders associated with this genotype. We conclude that there are several differences in basal brain metabolism according to the genetic variation in the SLC6A4 polymorphism and the cerebral pattern of activation is more widely distributed in the S/S carrier subjects. These results could help to explain the role of serotonin system in the liability to specific temperament traits or psychiatric disorders.
