Less NMDA Receptor Binding in Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex Associated With Reported Early-Life Adversity but Not Suicide

Abstract Background Glutamate is an excitatory neurotransmitter binding to 3 classes of receptors, including the N-methyl, D-aspartate (NMDA) receptor. NMDA receptor binding is lower in major depression disorder and suicide. NMDA receptor blocking with ketamine can have antidepressant and anti-suicide effects. Early-life adversity (ELA) may cause glutamate-mediated excitotoxicity and is more common with major depression disorder and in suicide decedents. We sought to determine whether NMDA-receptor binding is altered with suicide and ELA. Methods A total 52 postmortem cases were organized as 13 quadruplets of suicide and non-suicide decedents matched for age, sex, and postmortem interval, with or without reported ELA (≤16 years). Tissue blocks containing dorsal prefrontal (BA8), dorsolateral prefrontal (BA9), or anterior cingulate (BA24) cortex were collected at autopsy. Psychiatrically healthy controls and suicide decedents underwent psychological autopsy to determine psychiatric diagnoses and details of childhood adversity. NMDA receptor binding was determined by quantitative autoradiography of [3H]MK-801 binding (displaced by unlabeled MK-801) in 20-µm-thick sections. Results [3H]MK-801 binding was not associated with suicide in BA8, BA9, or BA24. However, [3H]MK-801 binding with ELA was less in BA8, BA9, and BA24 independent of suicide (P < .05). [3H]MK-801 binding was not associated with age or postmortem interval in any brain region or group. Conclusions Less NMDA receptor binding with ELA is consistent with the hypothesis that stress can cause excitotoxicity via excessive glutamate, causing either NMDA receptor downregulation or less receptor binding due to neuron loss consequent to the excitotoxicity.

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Association of BDNF Val66Met Polymorphism and Brain BDNF levels with Major Depression and Suicide

10.1101/233304 ◽

2017 ◽

Author(s):

Mariam M. Youssef ◽

Mark D. Underwood ◽

Yung-Yu Huang ◽

Shu-chi Hsiung ◽

Yan Liu ◽

...

Keyword(s):

Major Depression ◽

Early Life ◽

Childhood Adversity ◽

Anterior Cingulate ◽

Bdnf Expression ◽

Early Life Adversity ◽

Val66met Polymorphism ◽

Protein Levels ◽

Dorsolateral Prefrontal ◽

Bdnf Val66met Polymorphism

ABSTRACTBrain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depressive disorder (MDD) and suicide. Both are partly caused by early life adversity (ELA) and ELA reduces both BDNF protein and gene expression. This study examines the association of BDNF Val66Met polymorphism and brain BDNF levels with depression and suicide. We hypothesized that both MDD and ELA would be associated with the Met allele and lower brain BDNF levels. Such an association would be consistent with low BDNF mediating the effect of ELA on adulthood suicide and MDD. BDNF Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 non-suicides. Additionally, BDNF protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9; BA9), anterior cingulate cortex (ACC; BA24), caudal brainstem and rostral brainstem. The relationships between these measures and major depression, death by suicide and reported childhood adversity were examined. Depressed subjects had an excess of the Met allele and lower BDNF levels in ACC and caudal brainstem compared with non-depressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower BDNF levels in ACC were found in subjects who had been exposed to early life adversity and/or died by suicide compared to nonsuicide decedents and no reported childhood adversity. This study provides further evidence for low BDNF in major depression related to the BDNF met risk allele. Future studies should seek to determine how altered BDNF expression contributes to MDD and suicide.

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Early Life Adversity, but not suicide, is associated with less prefrontal cortex gray matter in adulthood

10.1101/531871 ◽

2019 ◽

Author(s):

Mark D. Underwood ◽

Mihran J. Bakalian ◽

Teresa Escobar ◽

Suham Kassir ◽

J. John Mann ◽

...

Keyword(s):

Prefrontal Cortex ◽

Early Life ◽

Suicide Risk ◽

Anterior Cingulate ◽

Psychological Autopsy ◽

Cell Nuclei ◽

Early Life Adversity ◽

Neuron Density ◽

Dorsolateral Prefrontal

AbstractBackgroundSuicide and major depression (MDD) are more prevalent in individuals reporting early life adversity (ELA). Prefrontal cortex volume is reduced by stress acutely and progressively in vivo, and changes in neuron and glia density are reported in depressed suicide decedents. We previously found reduced levels of the neurotrophic factor BDNF in suicide decedents and with ELA, and in the present study we sought to determine whether cortex thickness, neuron density or glia density in the dorsolateral prefrontal (BA9) and anterior cingulate (BA24) cortex are associated with ELA or suicide.MethodsA total of 52 brains, constituting 13 quadruplets of nonpsychiatric nonsuicide controls and MDD suicide decedents with and without ELA (n=13/group), all with psychological autopsy, were matched for age, sex and postmortem interval. Brains were collected at autopsy and frozen and blocks containing BA9 and BA24 were later dissected, post-fixed and sectioned. Sections were immunostained for NeuN to label neurons and counterstained with thionin to stain glial cell nuclei. Cortex thickness, neuron and glial density and neuron volume were measured by stereology.ResultsCortical thickness was 6% less with an ELA history in BA9 and 12% less in BA24 (p<0.05), but not in depressed suicide decedents in either BA9 or BA24. Neuron density was not different in ELA or in suicide decedents, but glial density was 17% greater with ELA history in BA9 and 15% greater in BA24, but not in suicides. Neuron volume was not different with ELA or suicide.DiscussionReported ELA, but not the stress associated with suicide, is associated with thinner prefrontal cortex and greater glia density in adulthood. ELA may alter normal neurodevelopment and contribute to suicide risk.

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Effect of cerebral hypoxia on NMDA receptor binding characteristics after treatment with 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) in newborn piglets

Brain Research ◽

10.1016/s0006-8993(96)00232-6 ◽

1996 ◽

Vol 729 (1) ◽

pp. 66-74

Author(s):

K Fritz

Keyword(s):

Nmda Receptor ◽

Receptor Binding ◽

Phosphonic Acid ◽

Cerebral Hypoxia ◽

Binding Characteristics ◽

Newborn Piglets ◽

Nmda Receptor Binding

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Effects of Long-Term Antipsychotic Treatment on NMDA Receptor Binding and Gene Expression of Subunits

Neurochemical Research ◽

10.1023/a:1022325116309 ◽

2003 ◽

Vol 28 (2) ◽

pp. 235-241 ◽

Cited By ~ 36

Author(s):

Andrea Schmitt ◽

Mathias Zink ◽

Bettina Müller ◽

Brigitte May ◽

Anne Herb ◽

...

Keyword(s):

Gene Expression ◽

Nmda Receptor ◽

Receptor Binding ◽

Antipsychotic Treatment ◽

Nmda Receptor Binding

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SUN-722 Liver Leptin Receptor Gene Network Moderates the Effects of Early Life Adversity on Anxiety and Depression Problems in Children and Adolescents

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1034 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Randriely Merscher Sobreira de Lima ◽

Barbara Barth ◽

Danusa Mar Arcego ◽

Euclides José de Mendonça Filho ◽

Sachin Patel ◽

...

Keyword(s):

Early Life ◽

Gene Network ◽

Child Behavior Checklist ◽

Cholesterol Metabolism ◽

Emotional Behavior ◽

Anterior Cingulate ◽

Polygenic Risk Score ◽

Emotional Symptoms ◽

Early Life Adversity ◽

Lepr Gene

Abstract Leptin is a hormone involved in the regulation of food intake, with receptors largely expressed centrally and peripherally, in structures like the hypothalamus and the liver. Beyond its well-known actions as an energy-balance regulator, leptin is linked to psychiatric disorders. Considering that the association between genetic and early environmental factors contributes to psychopathology, disruptions of leptin signaling could be a key mechanism in this interaction. To investigate this possibility, we created an expression-based polygenic risk score (ePRS) reflecting variations in the function of the LepR gene network in the liver and hypothalamus, and investigated its interaction with postnatal adversity on Child Behavior Checklist in 4 years old children (main cohort: MAVAN, N=137) and 17 years old teenagers (Replication Cohort: ALSPAC, N=2630). There is an interaction effect between adversity exposure and liver-based LepR-ePRS, increasing depressive and anxiety problems on the MAVAN cohort (β=78.16, p=0.02, β=83.77, p=0.01). In ALSPAC, the results were replicated, showing an interaction between adversity exposure and liver-based LepR-ePRS, increasing the depression score and somatic symptoms (β=24.65, p=0.005; β=33.51, p=0.009). No significant interactions were found using the hypothalamus-based LepR-ePRS (p>0.05), suggesting specificity for the liver LepR gene network to predict these behavioral outcomes. A parallel-independent component analysis showed relationships between the SNPs from the liver ePRS-LepR and gray matter density in cortical areas involved in emotion regulation (middle frontal gyrus, inferior parietal lobule and anterior cingulate). Finally, the relationship between gene and MRI components in this analysis is moderated by the history of early life adversity exposure. Enrichment analysis of the liver LepR co-expression network shows that these genes are related to biological processes including regulation of glucose transport, cholesterol metabolism and cellular glucose homeostasis, which indicates possible underlying mechanisms linking peripheral metabolism-related gene expression and the development of emotional symptoms. Our data supports the hypothesis that exposure to early adversity affects emotional behavior, and the liver LepR gene network is an important moderator of these effects. Further studies on development of emotional symptoms should consider metabolic markers to understand these complex phenotypes.

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