1) Deciphering the signaling pathways and transcriptional networks leading to the generation of serotonergic neurons
In all vertebrates, serotonergic neurons are found in the raphe nuclei of the hindbrain, which give rise to ascending and descending tracts supplying serotonergic fibers to the entire CNS. In fish, serotonergic neurons are present in several additional regions, including hypothalamus. Several signaling pathways, including for instance Fgf, Hedgehog and Wnt, are known to play a role for the developmental generation of serotonergic neuron populations. We have previously shown that the ETS-domain transcription factors Pet1 and Etv5b are important for distinct serotonergic populations, and hence provide support for the existence of a developmental heterogeneity among serotonergic cells in their requirement for ETS-domain transcription factors. We are currently further exploring the signaling pathways and transcriptional networks relevant for this process.
2) Ultrastructural investigations of serotonergic release sites
The serotonergic innervation of the brain is diffuse and modulatory in its character and most, if not all, cells in the brain are under serotonergic influence. Accordingly, there is evidence that serotonin is mostly released outside the synapse and diffuses with the cerebrospinal fluid over longer distances, i.e. acting by “volume transmission”. In collaboration with Dr. Christian Stigloher, Biocenter Imaging Core Facility, we are investigating the ultrastructure of serotonergic release sites and are thereby providing a detailed structural comparison of synaptic versus non-synaptic sites.
3) Testing the role of genes implicated in developmental psychiatric disorders
A large number of genes have been linked to psychiatric disorders in humans, but in many cases a functional explanation is missing. The zebrafish is an ideal model to address such issues because pharmacological and genetic tools to manipulate the function of serotonin are available and can be applied at any developmental stage in live animals, the embryos are developing outside of the mother’s body and therefore developmental processes can be visualized in real time and brain development in this organism has been extensively studied. We are using genetic tools to target some genes implicated in human psychiatric disorders in zebrafish followed by neuroanatomical investigations and evaluations of the behavioral consequences.