Thesis defense Yvet Kroeze (Donders thesis series 305)
Promotor: prof. dr.H. van Bokhoven, copromotors: dr. J. Homberg, dr. H. Zhou
Effects of serotonin signaling on behavior and gene transcription
A journey through postnatal brain development
Aberrant serotonin (5-HT) signaling is involved in several affective disorders, and drugs used for the treatment of affective disorders are often targeting the 5-HT system. It is known that 5-HT is involved in the pathophysiology of affective disorders, but it is still unclear how (changes in) 5-HT signaling can affect behavior. The aim of this thesis was to unravel the behavioral and molecular consequences of aberrant 5-HT signaling across postnatal development. We studied the long-term effects of selective serotonin reuptake inhibitors (SSRIs; blocking the serotonin transporter (5-HTT)) on genome-wide gene expression in the hippocampus of adult rats 40 days after SSRI exposure and showed that the expression of myelination-related genes was significantly upregulated in the hippocampus. In addition, we showed that expression of myelination-related genes in the hippocampus of adult rats postnatally exposed to SSRIs was significantly decreased. These opposite findings on gene expression fit with the opposite age-dependent effects on anxiety and depression-like behavior found by others. Next, we studied early-life behavior in rats with a reduction in functional 5-HTT and found a delay in development, especially on motor coordination and reflex development. Furthermore, we examined genome-wide expression in the developing medial prefrontal cortex in wildtype and in 5-HTT knockout rats and identified a clear genetic switch from neuronal network establishment in infancy to maintenance in adulthood (in both groups). In addition, we compared gene expression in wildtype and 5-HTT knockout rats and observed most expression changes on the earliest time point we measured (postnatal day (PND)8) and found an enrichment of genes linked to neurotransmission and cell migration in this group of genes. In conclusion, our experimental observations support the existing literature on the age-dependent effects of SSRIs and contribute to an increased insight into the effects of 5-HT on behavior and gene expression during different developmental stages.