Exposure to stress, particularly early in life, is a risk factor for a number of psychiatric illnesses in adult life, including schizophrenia and depression. In this plenary session from ECNP 2021, Annamaria Cattaneo (University of Milan, Italy) presented current thinking on the underling molecular mechanisms affected by early life adversities, and how this may lead to a vulnerable phenotype. Discovering novel vulnerability genes and clinical biomarkers open up the possibility of identifying those individuals most at risk, and targeting and developing appropriate interventions.
Early life stress exposure can have life-long effects
Adverse childhood experiences include exposure to maternal mental illness, abuse and natural disasters. An important aspect is that not all individuals who are exposed develop mental illness later in life. This depends on timing, duration and severity of the adverse event, as well as genetic vulnerability, and other environmental and lifestyle factors.
Early life stress exposure can have life-long effects and the most vulnerable periods are prenatal and childhood
The most vulnerable periods are prenatal and childhood. Events and exposures during these temporal windows seem to have the most profound effects on the neurodevelopment trajectory and shaping the individual into who they will be as adults. The newborn period is usually associated with photos of a smiling baby and mother, but this is not true for the percentage of women who suffer from postpartum depression. This impacts the relationship between mother and baby, and also the child’s emotional development.
Impact of maternal prenatal depression on the child
Neuroimaging studies demonstrate changes in the child’s brain development following fetal exposure to maternal depression
Maternal depression during pregnancy may be even more important, in terms of biological alterations affecting the foetal environment, and hence the neurodevelopment and vulnerability of the offspring. Neuroimaging studies, using structural and functional MRI, demonstrate changes in the child’s brain development including cortical thinning1 and increased amygdala responses to negative emotional faces2, following fetal exposure to maternal depression. A meta-analysis of maternal prenatal depression and anxiety on child’s socioemotional development up to 18 years3, demonstrated adverse effects on the child, including behavioural dysregulation, with an odds ratio of 1.79.
Role of inflammation and the stress response
Pregnant women with depressive symptoms, or at high risk of depression, show alterations in biological processes related to inflammation and the stress response
Dr Cattaneo presented unpublished work showing that pregnant women with depressive symptoms, or at high risk of depression (previous history of depression or childhood trauma), show alterations in biological processes related to inflammation and the stress response. A panel of cytokines from maternal serum at Week 25 gestation demonstrated changes, in both women with depression, and those at high risk of depression, compared to controls. Transcriptomic analyses identified a list of candidate genes that were significantly modulated in depressed and/or high-risk women, compared to controls, and these are involved in pathways related to depression. Changes are not confined to mothers. The offspring of women who were depressed, and those at high risk of depression, showed reductions in measures, such as social interaction and motor skills, in the Neonatal Behavioral Assessment Scale test at 6 days.
Potential mechanisms and biomarkers
Dr Cattaneo went on to discuss how results from clinical cohorts are being used in preclinical models to identify potential mechanisms and biomarkers. The rodent prenatal stress (PNS) model has supported the role of stress- and inflammation-related processes as mechanisms affected by stress early in life and underlying the development later in life of a vulnerable phenotype. This may occur via activation of epigenetic mechanisms such as methylation4. The micro RNA miR30a has been identified as a potential biomarker of childhood trauma-associated depression5. Modulation of neuronal plasticity may also play a part6. Reduced brain-derived neurotrophic factor (BDNF) levels have been found in the brain of adult PNS rats7, and low plasma BDNF levels and childhood neglect are associated with verbal memory impairment in depression8.
Fox01, a novel gene, is being studied as a biomarker to map vulnerable individuals and track treatment efficacy
A cross species and cross tissues approach has allowed the identification of novel pathways and vulnerability genes for gene X environment interaction studies in depression. Fox01 is one such novel gene9. It has now been studied as a biomarker to map vulnerable individuals and track treatment efficacy. In the Atlanta Grady Trauma and Helsinki Birth Cohort Studies, Fox01 genetic variability mediated the effects of childhood trauma/emotional stress on the development of depressive symptoms in adults10. Dr Cattaneo also showed (unpublished data) that Fox01 mRNA levels correlate with treatment response, following metacognitive interpersonal therapy, in patients with borderline personality disorder and a history of childhood trauma.
