Translational psychiatry; the twists and turns of early life stress and serotonin transporter gene variation

Major depressive disorder, commonly referred to as (unipolar) depression, is a psychiatric disorder that inflicts a huge personal and societal burden, and, according to the World Health Organization, is among the leading causes of disability worldwide. Over the past decade it has becoming increasingly clear that vulnerability to depression consists of a complex interplay of genome and environment. A well-studied example of gene x environment interaction in psychiatry involves the serotonin (5-hydroxytryptamine; 5-HT) transporter gene. The short allele of the 5-HTT-linked polymorphic region has been associated with reduced expression of the 5-HTT gene, and increased risk to develop depression after early life exposure to stress. For this thesis, we studied the biological and behavioural consequences of the interaction between 5-HTT gene variation and early life stress exposure. To perform these studies, we have subjected 5-HTT homozygous and heterozygous knockout rats during the early postnatal life to repeated and prolonged separations from their mothers. Our major conclusions: 1) The short allele of the 5-HTT gene does not only confer increased vulnerability to stress-induced depression, but - when stress is mild - can also be associated with increased stress resilience. 2) We found that the interaction of 5-HTT gene variation and early life stress also affects the hypothalamo-pituitary-adrenal (HPA) axis, specifically at the level of the adrenals. The HPA-axis is responsible for the regulation of glucocorticoid levels in the blood, which function to coordinate energy availability, behaviour, learning and memory during the response to stress