BDNFVal66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields

Frodl, Thomas; Skokauskas, Norbert; Frey, Eva-Maria; Morris, Derek W.; Gill, Michael; Carballedo, Angela

doi:10.1002/hbm.22584

Cited by 74 publications

(44 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, gross volumetric differences might not be as sensitive as effects on subregions. For instance, a recent study in adults reporting histories of childhood trauma found trauma-by-BDNF effects on specific subregions of the hippocampus (i.e., CA2/3; Frodl, Skokauskas et al 2014). Continued research will address regional specificity and cellular changes that underlie structural MRI GMV differences, and will contribute understanding to how BDNF modulates limbic brain structures over the course of development.…”

Section: Discussionmentioning

confidence: 99%

Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood

Marusak

Kuruvadi

Vila

et al. 2015

Eur Child Adolesc Psychiatry

View full text Add to dashboard Cite

Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer-term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood

Marusak

Kuruvadi

Vila

et al. 2015

Eur Child Adolesc Psychiatry

View full text Add to dashboard Cite

show abstract

“…This is a functional SNP that reduces the processing of pro-BDNF to mature BDNF decreases BDNF transport to terminals, and thereby blocks activity dependent release of BDNF. The BDNF Met allele has been associated with reduced hippocampal volume and executive function in humans [28, 29] and increased risk for depression in patients exposed to early life stress or trauma [32, 45, 54]. BDNF Met knock-in mice display a reduction in the number and length of branch points of CA3 pyramidal neurons in the hippocampus (spine density was not examined) [57].…”

Section: Mechanisms Underlying Dendrite and Spine Deficits Caused By mentioning

confidence: 99%

Spine synapse remodeling in the pathophysiology and treatment of depression

Duman

2015

Neuroscience Letters

226

184

View full text Add to dashboard Cite

Clinical brain imaging and postmortem studies provide evidence of structural and functional abnormalities of key limbic and cortical structures in depressed patients, suggesting that spine synapse connectivity is altered in depression. Characterization of the cellular determinants underlying these changes in patients are limited, but studies in rodent models demonstrate alterations of dendrite complexity and spine density and function that could contribute to the morphological and functional alterations observed in humans. Rodent studies demonstrate region specific effects in chronic stress models of depression, including reductions in dendrite complexity and spine density in the hippocampus and prefrontal cortex (PFC) but increases in the basolateral amygdala and nucleus accumbens. Alterations of spine synapse connectivity in these regions are thought to contribute to the behavioral symptoms of depression, including disruption of cognition, mood, emotion, motivation, and reward. Studies of the mechanisms underlying these effects demonstrate a role for altered brain derived neurotrophic factor (BDNF) signaling that regulates synaptic protein synthesis. In contrast, there is evidence that chronic antidepressant treatment can block or reverse the spine synapse alterations caused by stress. Notably, the new fast acting antidepressant ketamine, which produces rapid therapeutic actions in treatment resistant MDD patients, rapidly increases spine synapse number in the PFC of rodents and reverses the effects of chronic stress. The rapid synaptic and behavioral actions of ketamine occur via increased BDNF regulation of synaptic protein synthesis. Together these studies provide evidence for a neurotophic and synaptogenic hypothesis of depression and treatment response and indicate that spine synapse connectivity in key cortical and limbic brain regions is critical for control of mood and emotion.

show abstract

“…The met-allele of the Val66Met Single-Nucleotide Polymorphism (SNP) of the BDNF gene, coding for a replacement of the amino acid valine (val) by methionine (met), has been associated with decreased activity-dependent secretion of BDNF (Egan et al , 2003; Chen et al , 2004). Previous studies investigating a BDNF gene by CM interaction have shown that Met-carriers of the BDNF gene with a history of CM have decreased volume of the anterior cingulate cortex (ACC) (Gerritsen et al , 2012), hippocampus (Molendijk et al , 2012; Carballedo et al , 2013; Frodl et al , 2014) and amygdala (Gatt et al , 2009) compared to met-carriers without CM and individuals with a val/val genotype, although again results have been inconsistent (Gerritsen et al , 2012). …”

Section: Introductionmentioning

confidence: 99%

Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology

Velzen

Schmaal

Jansen

et al. 2016

Soc Cogn Affect Neurosci

View full text Add to dashboard Cite

Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF.

show abstract

BDNFVal66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields

Cited by 74 publications

References 42 publications

Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood

Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood

Spine synapse remodeling in the pathophysiology and treatment of depression

Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology

Contact Info

Product

Resources

About