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326 REVERSIBLE DISORDERS OF BRAIN DEVELOPMENTRole of BDNF Gene Polymorphisms in Mood DisordersBrain-derived neurotrophic growth factor (BDNF) appears to be critical for regulatingneuronal survival during brain development (Poo, 2001) and may be involvedin response to antidepressants (D’Sa & Duman, 2002) and lithium (Hashimotoet al., 2002). A common functional polymorphism exists for BDNF as a single nucleotidepolymorphism (SNP) at codon 66 resulting in an amino acid change from val(val66) to met (val66met). Association studies have reported association of the vall66allele with BD (Neves-Pereira et al., 2002; Sklar et al., 2002), but another Japanesestudy was not able to replicate this finding (Nakata et al., 2003). However, linkagedisequilibrium of the vall66 allele recently was reported for a cohort of childrenwith prepubertal-onset BD (Geller et al., 2004), the first positive genetic finding ina childhood-onset BD cohort. Thus, it is possible that the val66 polymorphism isalso a gene of small but significant effect on BD development.Gene Effects on Brain Structure and FunctionThe 44-bp insertion/deletion polymorphism of 5-HTT may also directly affect brainstructure and function in regions thought to be involved in the pathophysiologyof BD. Using voxel-based morphometry techniques to study 114 healthy volunteers,Pezewas et al. (2005) reported that those carrying the 5-HTT s-allele hadreduced amygdalar and perigenual cingulate gray matter volume compared to l/lparticipants. Morphometric abnormalities do not necessarily imply functionalchanges. Nevertheless, amygdalar volume was found to be inversely correlated toamygdalar activation in one study of depressed adults (Siegle, Steinhauer, Thase,Stenger, & Carter, 2002). This finding supports the hypothesis that individualsat risk for BD with decreased amygdalar gray matter volume may also haveamygdalar overactivation during affective situations.Healthy carriers of the s-allele also have been found to have increased rightamygdalar activation when viewing fearful or angry faces, compared to thosewithout the s-allele (Hariri et al., 2005; Hariri et al., 2002). Negatively valencedstimuli (aversive pictures from the International Affective Pictures System, IAPS)caused greater amygdalar activation and greater coupling between amygdala andventromedial prefrontal cortex in healthy volunteer carriers of the s-allele comparedto noncarriers (Heinz et al., 2005). Furthermore, the number of s-alleles ineach individual was correlated with amount of amygdalar activation when viewingnegatively valenced pictures. In carriers of the s-allele, ventromedial PFC(vmPFC) activation was more strongly coupled to amygdalar activation and resultedin greater activation of vmPFC compared to those with the l/l genotype.These powerful findings suggest that modulations in serotonergic activity causedby 5-HTT gene polymorphisms affect degree of amygdalar and prefrontal activationin response to affective challenge. These findings imply that in individuals atrisk for BD, the 5-HTT s-allele may have pronounced effects on amygdalar structureand direct or indirect effects on amygdalar activation (figure 14-3).